Criminalization of substance use during pregnancy because of harm to the fetus or child is fiercely debated. [ 145 ] [ 146 ]  Elizabeth Armstrong has questioned the zero-tolerance approach taken towards alcohol consumption during pregnancy, describing it as a  moral panic . [ 147 ] [ 148 ]  While heavy alcohol consumption during pregnancy is known to be damaging to the unborn child, the effects of low intakes remain debatable, particularly in the absence of randomized controlled trials (c.f.  § Causes ). [ 44 ] [ 42 ]  The UK's abstinence recommendation was not chosen based on scientific evidence, but rather because it was simple advice that would ensure no one underestimated the risk. [ 149 ]  Tennessee's 2014 fetal assault law (which expired in 2016) was criticized for not addressing alcohol use. [ 150 ] [ 151 ]  The law criminalized opioid use during pregnancy and resulted in women avoiding professional medical care for fear of prosecution. [ 152 ]  A wide variety of professional organizations oppose criminalization. [ 153 ] [ 154 ]  Minnesota, North Dakota, Oklahoma, South Dakota, and Wisconsin have statutory authorization for the involuntary civil commitment of women who abuse alcohol during pregnancy. [ 155 ]


In 2016, a  CDC  press release and infographic entitled "More than 3 million US women at risk for alcohol-exposed pregnancy" caused controversy. [ 156 ]  The CDC release contained the message "The risk is real. Why take the chance?". [ 157 ] [ 158 ]  Darlena Cunha of Times Magazine interpreted the infographic as telling all women of child-bearing age not to drink at all, in case they might accidentally fall pregnant, and called them "scare tactics" and "shaming recommendations". [ 159 ]  Julie Beck said that the infographic insinuated that "your womb is a Schrodinger's box and you shouldn't pour alcohol into it unless you've peeked in there to be 100 percent sure the coast is clear". [ 160 ]  The CDC later clarified that the infographic was not intended to make any new guidelines or recommendations for women who are pre-pregnant, but rather to encourage conversations about alcohol with health professionals. [ 161 ]  Nonetheless, half of the pregnancies in developed countries and over 80% in developing countries are unplanned. Many women do not realize they are pregnant during the early stages and continue drinking when pregnant. [ 39 ]


In  Aldous Huxley 's 1932 novel  Brave New World  (where all fetuses are gestated  in vitro  in a factory), lower  caste  fetuses are created by receiving alcohol transfusions (Bokanovsky Process) to reduce intelligence and height, thus conditioning them for simple, menial tasks. Connections between alcohol and incubating embryos are made multiple times in the novel. [ 162 ]


The main character of the 2009 film  Defendor  is implied to have the condition. [ citation needed ]


Tony Loneman, a character in  Tommy Orange 's 2018 novel  There There , was born with fetal alcohol syndrome, which he calls "the Drome".


Fetal trimethadione syndrome  (also known as  paramethadione syndrome ,  German syndrome ,  tridione syndrome , among others [ 1 ] ) is a set of  birth defects  caused by the administration of the  anticonvulsants   trimethadione  (also known as Tridione) or  paramethadione  to epileptic mothers during  pregnancy . [ 2 ]


Fetal trimethadione syndrome is classified as a  rare disease  by the  National Institute of Health 's Office of Rare Diseases, [ 3 ]  meaning it affects less than 200,000 individuals in the  United States . [ 4 ]


The fetal  loss rate  while using trimethadione has been reported to be as high as 87%. [ 5 ]


Fetal trimethadione syndrome is characterized by the following major symptoms as a result of the  teratogenic  characteristics of trimethadione. [ 2 ] [ 6 ]


Surgery may help alleviate the effects of some physical defects, but prognosis is poor, especially for those with severe cardiovascular and cognitive problems. Speech and physical therapy, as well as  special education , is required for surviving children. [ 7 ]


Fetus  in fetu  (or  foetus  in foetu ) is a rare  developmental abnormality  in which a mass of tissue resembling a  fetus  forms inside the body of its  twin . An early example of the phenomenon was described in 1808 by George William Young. [ 1 ]


There are two hypotheses for the origin of a fetus  in fetu . One hypothesis is that the mass begins as a normal fetus but becomes enveloped inside its twin. [ 2 ]  The other hypothesis is that the mass is a highly developed  teratoma . Fetus  in fetu  is estimated to occur in 1 in 500,000 live births. [ 3 ]


A fetus  in fetu  can be considered alive, but only in the sense that its component tissues have not yet died or been eliminated. Thus, the life of a fetus  in fetu  is akin to that of a  tumor  in that its cells remain viable by way of normal metabolic activity. However, without the gestational conditions  in  utero  with the  amnion  and  placenta , a fetus  in fetu  can develop into, at best, an especially well  differentiated teratoma ; or, at worst, a high-grade  metastatic   teratocarcinoma . In terms of physical maturation, its organs have a working blood supply from the host, but all cases of fetus  in fetu  present critical defects, such as no functional brain, heart, lungs, gastrointestinal tract, or urinary tract. Accordingly, while a fetus  in fetu  can share select  morphological  features with a normal fetus, it has no prospect of any life outside of the host twin. Moreover, it poses clear threats to the life of the host twin on whom its own life depends. [ 4 ]


There are two main hypotheses about the development of fetus  in fetu .


Fetus  in fetu  may be a very highly differentiated form of  dermoid cyst , itself a highly differentiated form of  mature teratoma . [ 5 ]


Fetus  in fetu  may be a  parasitic twin   fetus  growing within its  host   twin . Very early in a  monozygotic  twin pregnancy, in which both fetuses share a common placenta, one fetus wraps around and envelops the other. The enveloped twin becomes a  parasite , in that its survival depends on the survival of the host twin, by drawing on the host twin's blood supply. The parasitic twin is  anencephalic  (without a  brain ) and lacks some  internal organs , and as such is unable to survive on its own. As the host twin has to "feed" the enveloped twin from the nutrients received over a single umbilical cord, they usually die before birth. [ citation needed ]


Fibrinogen deficiency , also known as  factor I deficiency , is a rare inherited bleeding disorder related to  fibrinogen  function in the  coagulation cascade . It is typically subclassified into four distinct  fibrinogen disorders : afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia, and hypodysfibrinogenemia. [ 1 ]


Clinically, these disorders are generally associated with an increased  diathesis , i.e. propensity, to develop spontaneous bleeding episodes and excessive bleeding after even minor tissue injuries and surgeries; however, individuals with any of these disorders may also exhibit a propensity to pathological  thrombosis  episodes. [ 4 ] [ 6 ]


Treatment of these disorders generally involves specialized centers and the establishment of preventive measures designed based on each individuals personal and family histories of the frequency and severity of previous bleeding and thrombosis episodes, and, in a select few cases, the predicted propensity of the genetic mutations which underlie their disorders to cause bleeding and thrombosis. [ 5 ] [ 6 ]


Afibrinogenemia is typically the most severe of the three disorders. Common symptoms include bleeding of the umbilical cord at birth, traumatic and surgical bleeding, GI tract, oral and mucosal bleeding, spontaneous splenic rupture, and rarely intracranial hemorrhage and articular bleeding. [ 2 ] [ 7 ]
Symptoms of hypofibrinogenemia varies from mild to severe, but can include bleeding of the GI tract, oral and mucosal bleeding, and very rarely intracranial bleeding. More commonly it presents during traumatic bleeding or surgical procedures. [ 2 ] [ 3 ]  Most cases (60%) of dysfibrinogenemia are asymptomatic, but 28% exhibit hemorrhaging similar to that described above while 20% exhibit thrombosis (i.e. excessive clotting). [ 3 ]


The disorders associated with Factor I deficiency are generally  inherited , [ 2 ] [ 3 ]  although certain liver diseases can also affect fibrinogen levels and function (e.g.  cirrhosis ). [ 8 ]  Afibrinogenemia is a recessive inherited disorder, where both parents must be carriers. [ 2 ]  Hypofibrinogenemia and dysfibrinogenemia can be dominant (i.e. only one parent needs to be a carrier) or recessive. [ 2 ]  The origin of the disorders is traced back to three possible genes: FGA, FGB, or FGG. Because all three are involved in forming the hexameric glycoprotein fibrinogen, mutations in any one of the three genes can cause the deficiency. [ 9 ] [ 10 ]


The most common type of treatment is  cryoprecipitate  a fibrinogen concentrate used in a  drip  to increase fibrinogen levels to normal during surgical procedures or after trauma. [ 11 ] [ 2 ]  RiaSTAP, a factor I concentrate, was approved by the U.S. FDA in 2009 for use when the fibrinogen level was below 50 mg/deciliter of plasma. [ 12 ]  Recently,  antifibrinolytics  have also been used to inhibit  fibrinolysis  (breaking down of the fibrin clot). [ 3 ]  In the case of dysfibrinogenemia that manifests by  thrombosis , anticoagulants can be used. [ 2 ]  Due to the inhibited clotting ability associated with a- and hypofibrinogenemia, anticoagulants including  aspirin  are advised against. [ 2 ]


Fibro-adipose vascular anomaly , also known as FAVA, is a type of vascular anomaly that is both rare and painful. FAVA is characterized by tough  fibrofatty  tissue taking over portions of muscle, most often contained within a single limb. FAVA also causes  venous  and/or  lymphatic  abnormalities. [ 1 ]


Though FAVA has only been recognized as a distinct vascular anomaly, separate from common  venous malformations , within the past ten years, FAVA a distinct  congenital disorder . [ 2 ]


Common symptoms of FAVA include severe pain and difficulty moving the affected limb, mild enlargement of the affected limb with visible veins, and  contracture . [ 1 ]


In the cohort described by Alomari et al. [ 2 ]  from the Vascular Anomalies Center at  Boston Children's Hospital , FAVA was located, in descending order, in the  calf ,  forearm / wrist  and  thigh . The most common presentation is severe  pain .  Calf lesions , particularly those located in the posterior compartment, are commonly associated with restricted ankle dorsiflexion (equinus contracture). [ citation needed ]


No one knows what causes FAVA, though recent research revealed mutations in a gene called PIK3CA in some—but not all—cases. [ 3 ]   PIK3CA  is a  gene  in the receptor tyrosine kinase phosphatidylinositol 3-kinase (PI3)-AKT growth-signaling pathway. The PIK3CA gene is located on the long (q) arm of  chromosome 3 . [ 4 ]


There has been no evidence to suggest that FAVA is inherited or passed along in families. [ 2 ] [ 1 ]


FAVA is most often diagnosed in older children, teens and young adults, though it has been diagnosed earlier and later in a patient's life. [ 1 ]


The constellation of clinical, radiologic, and  histopathologic  findings typically allow the diagnosis of FAVA. [ 5 ]  The most helpful imaging studies are  ultrasonography  (US) and  magnetic resonance imaging  (MRI). The major imaging features of FAVA include the presence of complex intramuscular solid  lesion  replacing normal muscle fibers with fibrofatty overgrowth and phlebectasia. The extrafascial part is composed of fatty overgrowth, phlebectasia, and occasional lymphatic malformation.
The histopathologic findings in FAVA include dense  fibrous tissue , fat, and lymphoplasmacytic aggregates within  atrophied  skeletal muscle.  Adipose tissue  within skeletal muscles are associated with large, irregular, and sometimes excessively muscularized venous channels and smaller, clustered channels. [ 2 ]  Organizing thrombi, lymphatic foci and enlarged nerves encircled by dense fibrous tissue are also frequently noted in FAVA. [ citation needed ]


Some FAVA patients develop limb  contracture ; in these cases early orthopedic consultation is necessary.  Achilles tendon  lengthening (heel-cord release) and  physical therapy  can be helpful for treating equinus contracture. [ 6 ]


Unlike classical venous malformations, pain in FAVA is multifactorial and clinical response to  sclerotherapy  of the venous component can be less effective. [ 7 ]  While intralesional  steroid  injections and nerve block may offer temporary or partial pain relief, the source of pain is often the solid intramuscular lesion.  Surgical resection  and image-guided percutaneous  cryoablation  may offer an effective control of pain in FAVA lesions. [ 8 ] [ 5 ]   Sirolimus  has been effective in improving the quality of life in some people with FAVA. [ 9 ]


Fibrochondrogenesis  is a rare [ 1 ]   autosomal   recessive [ 2 ]  form of  osteochondrodysplasia , [ 3 ]  causing abnormal fibrous development of  cartilage  and related  tissues . [ 4 ]


It is a lethal  rhizomelic  (malformations which result in short, underdeveloped limbs) form of  dwarfism , [ 1 ]  exhibiting both  skeletal dysplasia  (malformations of  bone ) and  fibroblastic dysplasia  (abnormal development of  fibroblasts , specialized  cells  that make up  fibrous connective tissue , which plays a role in the formation of cellular structure and promotes healing of damaged  tissues ). [ 4 ] [ 5 ] [ 6 ]  Death caused by complications of fibrochondrogenesis occurs in  infancy . [ 6 ]


Fibrochondrogenesis is a  congenital disorder  presenting several features and  radiological  findings, some which distinguish it from other osteochondrodysplasias. [ 7 ]  These include: fibroblastic dysplasia and  fibrosis  of  chondrocytes  (cells which form cartilage); [ 4 ] [ 5 ]  and flared, widened
 long bone   metaphyses  (the portion of bone that grows during childhood). [ 6 ] [ 8 ]


Other prominent features include dwarfism, [ 1 ]  shortened  ribs  that have a  concave  appearance, [ 6 ]   micrognathism  (severely underdeveloped  jaw ), [ 7 ]   macrocephaly  (enlarged head), [ 8 ]   thoracic   hypoplasia  (underdeveloped chest), [ 8 ]  enlarged  stomach , [ 8 ]   platyspondyly  (flattened  spine ), [ 6 ]  and the somewhat uncommon deformity of  bifid   tongue  (in which the tongue appears split, resembling that of a  reptile ). [ 7 ]


The cause of platyspondyly in fibrochondrogenesis can be attributed in part to odd malformations and structural flaws found in the  vertebral bodies  of the spinal column in affected infants. [ 4 ] [ 6 ]


Fibrochondrogenesis alters the normal function of chondrocytes, fibroblasts, metaphyseal cells and others associated with cartilage, bone and  connective tissues . [ 2 ] [ 3 ] [ 4 ]  Overwhelming
disorganization of cellular processes involved in the formation of cartilage and bone ( ossification ), in combination with fibroblastic degeneration of these cells, developmental errors and systemic skeletal malformations describes the severity of this lethal osteochondrodysplasia. [ 3 ] [ 4 ] [ 6 ] [ 8 ]


Fibrochondrogenesis is inherited in an autosomal recessive pattern. [ 4 ]  This means that the defective  gene  responsible for the disorder is located on an  autosome , and two copies of the gene — one copy inherited from each parent — are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder each  carry  one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder. Currently, no specific genetic  mutation  has been established as the cause of fibrochondrogenesis. [ 9 ]


Omphalocele  is a congenital feature where the  abdominal wall  has an opening, partially exposing the  abdominal viscera  (typically, the  organs  of the  gastrointestinal tract ). Fibrochondrogenesis is believed to be related to omphalocele
type III, suggesting a possible genetic association between the two disorders. [ 10 ]


Fibrochondrogenesis is quite rare. [ 1 ]  A 1996 study from  Spain  determined a national minimal prevalence for the disorder at 8 cases out of 1,158,067 live births. [ 11 ]


A  United Arab Emirates  (UAE)  University  report, from early 2003, evaluated the results of a 5-year study on the occurrence of a broad range of osteochondrodysplasias. [ 12 ]  Out of 38,048 newborns in  Al Ain , over the course of the study period, fibrochondrogenesis was found to be the most common of the recessive forms of osteochondrodysplasia, with a prevalence ratio of 1.05:10,000 births. [ 12 ]


While these results represented the most common occurrence within the group studied, they do not dispute the rarity of fibrochondrogenesis. The study also included the high rate of  consanguinous marriages  as a prevailing factor for these disorders, as well as the extremely low rate of diagnosis-related  pregnancy terminations  throughout the region. [ 12 ]


The fibrocartilaginous effects of fibrochondrogenesis on chondrocytes has shown potential as a means to produce  therapeutic  cellular  biomaterials  via  tissue engineering  and manipulation of  stem cells , [ 13 ] [ 14 ]  specifically  human   embryonic   stem cells . [ 13 ]


Utilization of these cells as curative cartilage replacement materials on the cellular level has shown promise, with beneficial applications including the repair and healing of damaged  knee   menisci  and  synovial joints ;  temporomandibular joints , and  vertebra . [ 13 ] [ 14 ] [ 15 ]


Fibrodysplasia ossificans progressiva  ( / ˌ f aɪ b r oʊ d ɪ ˈ s p l eɪ ʒ ( i ) ə   ɒ ˈ s ɪ f ɪ k æ n z   p r ə ˈ ɡ r ɛ s ɪ v ə / ; [ 1 ]   abbr.   FOP ),  also called  Münchmeyer disease  or formerly  myositis ossificans progressiva , is an extremely rare  connective tissue disease  in which fibrous  connective tissue  such as  muscle ,  tendons , and  ligaments  turn into  bone  tissue ( ossification ). It is the only known medical condition where one  organ system  changes into another. [ 2 ]  It is a severe, disabling disorder with no cure.


FOP is caused by a  mutation  of the gene  ACVR1 . The mutation affects the body's repair mechanism, causing  fibrous tissue  including  muscle ,  tendons , and  ligaments  to become  ossified , either spontaneously or when damaged as the result of trauma. In many cases, otherwise minor injuries can cause  joints  to become permanently fused as new bone forms, replacing the damaged muscle tissue. This new bone formation (known as "heterotopic ossification") eventually forms a secondary skeleton and progressively restricts the patient's ability to move. Bone formed as a result of this process is identical to "normal" bone, simply in improper locations. Circumstantial evidence suggests that the disease can cause joint degradation separate from its characteristic bone growth. [ 3 ]


Surgical removal of the extra bone growth has been shown to cause the body to "repair" the affected area with additional bone. Although the rate of bone growth may differ depending on the patient, the condition ultimately leaves sufferers immobilized as new bone replaces musculature and fuses with the existing skeleton. This has earned FOP the nickname " stone man disease ". [ 4 ]


For unknown reasons, children born with FOP often have malformed  big toes , sometimes missing a joint or, in other cases, simply presenting with a notable lump at the minor joint. [ 5 ]  The first "flare-up" that leads to the formation of FOP bone usually occurs before the age of 10. [ 5 ]  The bone growth generally progresses from the top of the body downward, just as bones grow in fetuses. A child with FOP will typically develop additional bones starting at the neck, then at the shoulders, arms, chest area, and finally at the feet. [ 6 ]


Specifically, ossification is typically first seen in the dorsal, axial, cranial, and proximal regions of the body. Later, the disease progresses in the ventral, appendicular, caudal, and distal regions. [ 5 ]  However, it does not necessarily occur in this order due to injury-caused flare-ups. Often, the tumor-like lumps that characterize a flare-up of the disease appear suddenly.


Bone growth occurring during flare-ups may result in the loss of mobility to affected joints, including, if the jaw/mandible is involved, the inability to fully open the mouth, limiting speech and eating. A specific occurrence of a flare-up of this condition in the foot/ankle joints can result in the limited ability to put a foot flat on the ground. [ citation needed ]  Bone growth can also result in the immobilization of the hip or knee, affecting the individual's ability to walk. Extra bone formation around the rib cage restricts the expansion of lungs and diaphragm causing respiratory complications. [ 5 ]


Since the disorder is incredibly rare, only occurring in 1 out of 2 million people, the condition may be misdiagnosed as  cancer  or  fibrosis . Misdiagnoses can lead  physicians  to order  biopsies , potentially exacerbating the growth of FOP bone. [ 7 ]  The presence of malformed toes or thumbs in those born with FOP helps distinguish this disorder from other skeletal problems. [ 8 ]


With proper medical management the median age of survival is 40 years. However, delayed diagnosis, trauma, and infections can decrease life expectancy. [ 9 ]


FOP is caused by an  autosomal   dominant allele  on chromosome 2q23-24. [ 10 ]  The allele has variable  expressivity , but complete  penetrance . Most cases are caused by spontaneous mutation in the  gametes ; most people with FOP cannot or choose not to have children.  A similar but less catastrophic disease is  fibrous dysplasia , which is caused by a  post-zygotic mutation .


A mutation in the gene  ACVR1  (also known as activin-like kinase 2 (ALK2)) is responsible for the disease. [ 10 ]  ACVR1 encodes  activin  receptor type-1, a  BMP  type-1 receptor. The mutation causes substitution of  codon  206 from  arginine  to  histidine  in the ACVR1 protein. [ 11 ] [ 12 ]  This substitution causes abnormal activation of ACVR1, leading to the transformation of connective tissue and muscle tissue into a secondary skeleton. This causes  endothelial cells  to transform to  mesenchymal stem cells  and then to bone. [ 13 ]
Normally, the ACVR1 gene encodes the activin receptor type-1 transmembrane  kinase  that bind BMP receptors (Type I BMPR and Type II BMPR) for  chondrogenesis  signaling. BMPs belong to a superfamily of proteins known as Transforming growth factor-beta ( TGF- β ) proteins. The binding of ACVR1 protein to BMP receptors start a signaling cascade that is crucial for inducing  endochondral  bone formation during development, as well as, skeletal and tissue  homeostasis . [ 14 ]


FOP is an  autosomal dominant  disorder. Thus, a child of an affected heterozygous parent and an unaffected parent has a 50% probability of being affected. Two affected individuals can produce unaffected children. Two unaffected individuals can produce an affected offspring as a result of the mutation of the gene. The homozygous dominant form is more severe than the heterozygous form. [ 15 ]


The protein that causes ossification is normally deactivated by an inhibitory protein after a fetus's bones are formed in the womb, but in patients with FOP, the protein keeps working. Aberrant bone formation in patients with FOP occurs when injured connective tissue or muscle cells at the sites of injury or growth incorrectly express an enzyme for bone repair during  apoptosis  (self-regulated cell death), resulting in lymphocytes containing excess  bone morphogenetic protein 4  (BMP4) provided during the immune system response. The bone that results occurs independently of the normal skeleton, forming its own discrete skeletal elements.  These elements, however, can fuse with normal skeletal bone. [ 16 ]  The diaphragm, tongue, and extra-ocular muscles are spared in this process, as well as cardiac and  smooth muscle . [ 5 ]  Since the incorrect enzyme remains unresolved within the immune response, the body continues providing the incorrect BMP4-containing lymphocytes. BMP4 is a product that contributes to the development of the skeleton in the normal embryo. [ 17 ]


The  ACVR1  gene encodes a bone morphogenic protein (BMP) receptor; this gene is mutated in FOP. It is responsible for growth and development of bone and muscles. The typical mutation, R202H, makes the inhibitor  FKBP1A  bind less tightly to the activation GS-loop. [ 18 ]  The result is that ACVR1 is not effectively turned off, and an overgrowth of bone and cartilage and fusion of joints occurs. [ 19 ]  Atypical mutations involving other residues work similarly. In some cases, the receptor can end up signalling that it's active without being bound to its activating ligand. [ 20 ]


Most cases of FOP are the result of a new gene mutation: these people had no history of this particular disorder in their family. There are some cases where the individual has inherited the mutation from one affected parent. [ 19 ]


Generally, FOP can be diagnosed with  radiographs . Early diagnosis of this disorder through radiology is very important to avoid unnecessary invasive investigations like  biopsies . The smallest or trivial trauma or intramuscular injections can amplify progression of the disease through inflammation hence the favorability of radiology. Clinicians should be aware of this rare entity, as it is frequently misdiagnosed as cancer or other benign entities such as infection, resulting in biopsies that can often hasten disease progression. [ 21 ]


Outbreaks may be measurable clinically by elevated levels of  alkaline phosphatase  and  bone-specific alkaline phosphatase . [ 22 ]  Another telltale sign of FOP is a shortened great toe with a malformed distal first metatarsal and a missing or abnormal first phalanx and/or interphalangeal joint. [ 23 ]


While FOP remains without a cure, a promising breakthrough lies in the approved treatment, Sohonos ( palovarotene ). [ 24 ]  Notably, attempts to surgically remove bone in a FOP patient may result in explosive growth of new bone. [ 25 ]  While undergoing  anesthesia , people with FOP may encounter difficulties with  intubation ,  restrictive pulmonary disease , and changes in the  electrical conduction system of the heart . [ 26 ]  Activities that increase the risk of falling or soft tissue injury should be avoided, as even minor trauma may provoke  heterotopic ossification . [ 27 ]  Intramuscular injections, including immunizations, should likewise be avoided in individuals with FOP, as these can also trigger ossification  [ 28 ]


Although there are no effective definitive treatments of the disorder, there are intermittent treatments such as anti-inflammatory drugs to suppress  inflammation  as a result of flare-ups or inflammation from muscle damage. Currently, surgery is not usually recommended for people with FOP as it can incite rapid bone formation at incision sites or where sutures have been applied to muscle or connective tissue. Life-saving surgery may be considered, however developing a surgical plan with input from a FOP specialist may be considered best practice. Surgical release of joint contractures is generally unsuccessful and risks new, trauma-induced heterotopic ossification. [ 29 ]


Antisense-mediated therapy, specifically using allele-selective LNA gapmers, has emerged as a promising strategy for FOP [ 30 ] . This approach targets the mutated ACVR1 gene, which causes heterotopic ossification by responding aberrantly to activin A. In recent studies, LNA gapmers effectively reduced the expression of the pathogenic ACVR1R206H transcript while sparing the wild-type ACVR1 gene, thus selectively suppressing osteogenic differentiation associated with FOP. This novel antisense approach offers potential for therapeutic application in FOP, representing a breakthrough in targeted genetic treatment for this and potentially other autosomal dominant disorders


As of 2017 [update] , approximately 800 cases of FOP have been confirmed worldwide, making FOP one of the rarest diseases known. [ 31 ]  The estimated  incidence  of FOP is 0.5 cases per million people and affects all ethnicities. [ 31 ]


Medical reports describing individuals affected by FOP date back to Dr.  Guy Patin  in 1692. [ 31 ]  FOP was originally called myositis ossificans progressiva and was thought to be caused by muscular inflammation ( myositis ) that caused bone formation. [ 31 ]  The disease was renamed by  Victor A. McKusick  in 1970 following the discovery that soft tissue other than muscles (e.g.  ligaments ) were also affected by the disease process. [ 31 ]


The best known FOP case is that of  Harry Eastlack  (1933–1973). His condition began to develop at the age of ten, and by the time of his death from pneumonia in November 1973, six days before his 40th birthday, his body had completely ossified, leaving him able to move only his lips. Eastlack never met another person with FOP during his lifetime. [ 32 ]


Eastlack donated his body to science and his skeleton is now at the  Mütter Museum  in  Philadelphia , and has proven to be an invaluable source of information in the study of FOP. Another person with FOP,  Carol Orzel  (April 20, 1959 – February 2018), also donated her body to the museum and her skeleton was placed on exhibit there, adjacent to Eastlack's, in February 2019. [ 33 ] [ 34 ]


Clinical trials of  isotretinoin ,  etidronate  with oral  corticosteroids , and  perhexiline  maleate have failed to demonstrate effectiveness, though the variable course of the disease and small prevalence induces uncertainty. [ 22 ]


A handful of pharmaceutical companies focused on rare diseases are currently in varying stages of investigation into different therapeutic approaches for FOP.


In August 2015, the U.S.  Food and Drug Administration  (FDA) Office of Orphan Products Development granted La Jolla Pharmaceuticals  orphan drug  designation for two novel compounds for FOP. The compounds are small-molecule  protein kinase inhibitors  designed to selectively block ACVR1 (ALK2). [ 40 ]


In August 2015,  Clementia Pharmaceuticals  also began the enrollment of children (ages 6 and above) into its Phase II clinical trial investigating  palovarotene  for the treatment of FOP. [ 41 ]  Preclinical studies demonstrated that palovarotene, a retinoic acid receptor gamma agonist, blocked abnormal bone formation in animal models by inhibition of secondary messenger systems in the BMP pathway. [ 42 ]  Clementia licensed palovarotene from Roche Pharmaceuticals, which previously evaluated the compound in more than 800 individuals including healthy volunteers and patients with chronic obstructive pulmonary disease. Palovarotene received Fast Track designation from the FDA and orphan designations for the treatment of FOP from both the FDA and the  European Medicines Agency  (EMA). [ 41 ]


In September 2015,  Regeneron  announced new insight into the mechanism of disease involving the activation of the ACVR1 receptor by activin A. In 2016, the company initiated a phase 1 study of its activin antibody,  REGN 2477 , in healthy volunteers; a phase 2 trial in FOP patients was conducted in 2017. [ 43 ]


Another potential therapeutic approach involves allele-specific  RNA interference  that targets mutated mRNA for degradation while preserving normal ACVR1 gene expression. [ 44 ]


Further investigation into the mechanisms of heterotopic bone formation in FOP could aid in the development of treatments for other disorders involving extra-skeletal bone formation.


Fibro/adipogenic progenitors (FAPs) may be the disease-causing cell type responsible for activin A dependent ectopic bone formation in both the muscles and tendons of mice bearing the FOP causing ACVR1(R206H) mutation. [ 45 ]


In December 2019,  Ipsen  issued a partial clinical hold for people under the age of 14, due to reports of early fusion of growth plates.


Recently, as of 2021 [update] , a potential therapeutic candidate,  saracatinib , is in phase III clinical trials as a potent heterotopic ossification inhibitor in wild-type and ACVR1 mutant mice. [ 46 ]


Filippi syndrome , also known as  Syndactyly  Type I with  Microcephaly  and Mental Retardation, is a very rare  autosomal recessive   genetic disease . [ 1 ]  Only a very limited number of cases have been reported to date. [ 2 ]  Filippi Syndrome is associated with diverse symptoms of varying severity across affected individuals, for example malformation of  digits ,  craniofacial abnormalities , intellectual disability, and growth retardation. [ 1 ]  The diagnosis of Filippi Syndrome can be done through clinical observation,  radiography , and  genetic testing . [ 2 ] [ 3 ]  Filippi Syndrome cannot be cured directly as of 2022, hence the main focus of treatments is on tackling the symptoms observed on affected individuals. [ 1 ] [ 2 ]  It was first reported in 1985. [ 4 ]


The symptoms of Filippi Syndrome can be  congenital  (apparent as an infant). [ 1 ]  The occurrence and severity of such symptoms are variable across affected individuals. [ 1 ] [ 2 ]  The progression of symptoms over one's lifetime has not been thoroughly studied due to the small number of people with Filippi Syndrome globally. [ 2 ]


Malformations of digits are expressed among people with Filippi Syndrome. [ 1 ]  One of the most common malformations is the webbing or fusion of digits, which is termed syndactyly. [ 1 ] [ 2 ] [ 5 ]  In particular, syndactyly of the third and fourth fingers or the second, third and fourth toes is termed "syndactyly type 1". [ 1 ]  The degree of syndactyly may differ across affected individuals, with some exhibiting syndactyly of  soft tissues  and skin only, and more severe cases exhibiting syndactyly of digital bones. [ 1 ]


Other malformations of digits include  clinodactyly  (curving) of the fifth fingers and  brachydactyly  (abnormal shortening) of digits. [ 1 ] [ 2 ]  Brachydactyly is believed to be largely due to abnormalities arising from the bones inside the hands and feet, specifically the  metacarpals  and  metatarsals . [ 1 ]


Furthermore, most people with Filippi Syndrome exhibit craniofacial abnormalities. [ 1 ]  Craniofacial abnormalities are birth defects observed at the head or face region of affected individuals. [ 6 ]  Some of the craniofacial abnormalities present in people with Filippi Syndrome include microcephaly (having a skull that is smaller than normal), prominent/ elevated  nasal bridge ,  hypertelorism  (having one's pair of eyes further apart from each other than normal), and underdeveloped nasal alae (underdeveloped tissues surrounding the  nostril ). [ 1 ] [ 2 ] [ 7 ]  Less common craniofacial abnormalities include having a broad forehead, thin  vermilion border  (having a thin upper lip), and  frontal  hirsutism (having a hairy forehead). [ 2 ]


People with Filippi Syndrome may also demonstrate varying degrees of  intellectual disability . [ 1 ] [ 2 ]  Affected individuals may experience defective speech development,  aphasia  (experiencing difficulty in finding the appropriate words to use), vision impairment, and an inability to speak. [ 1 ] [ 2 ]


Another characteristic symptom of people with Filippi Syndrome is the occurrence of growth retardation, which is also referred to as growth delay. [ 1 ] [ 2 ] [ 5 ]  Such growth delays may be either  prenatal  or  postnatal , meaning that they can occur both before and after birth. [ 1 ] [ 2 ]  In particular, delayed bone maturation can be observed in patients with Filippi Syndrome. [ 2 ]


People with Filippi Syndrome may exhibit some other physical abnormalities. Examples of such abnormalities include  dwarfism  (having a severely short stature), dislocated elbows, decreased joint mobility, muscular  hypotonia  (having weak  muscle tone ), and involuntary muscle stiffness. [ 1 ] [ 2 ]


They may also exhibit abnormal conditions at their skin and teeth. [ 1 ]  Moreover, a portion of affected males may demonstrate cryptorchidism (a condition in which the testes fail to descend into the scrotum). [ 1 ]


Filippi syndrome is a genetic disease with an autosomal recessive  inheritance  pattern at the Cytoskeleton Associated Protein 2 Like (CKAP2L)  gene . [ 1 ] [ 2 ] [ 7 ] [ 8 ]


An autosomal recessive inheritance pattern means that the disease trait is exhibited on an individual only when both copies of the disease gene in the individual demonstrate a specific pathogenic  mutation . [ 2 ]  This happens when the individual inherits one copy of the mutated gene from each of their parents. [ 2 ]  In the case of Filippi Syndrome, both copies of the CKAP2L gene of an individual have to be mutated in order for them to demonstrate symptoms of the disorder. [ 1 ] [ 2 ]


The CKAP2L gene is the human  ortholog  of the mouse CKAP2I (Radmis) gene. [ 9 ]  It contains 10  exons  and is located on  chromosome  2q14.1. [ 9 ]  It is a protein-coding gene that is associated with  microtubules  and some cellular structures involved in  mitosis . [ 9 ] [ 10 ]  The CKAP2L gene is essential for the proper formation of  mitotic spindles  during mitosis and the progression of the  cell cycle  of human cells. [ 10 ]  The expression pattern of the CKAP2L gene can explain the occurrence of syndactyly in Filippi Syndrome. [ 10 ]


Multiple mutations at the CKAP2L gene can cause Filippi Syndrome. Some of these mutations include a 1-base pair  duplication  in exon 4, a 2-base pair  insertion  in exon 2, a 1-base pair  deletion  in exon 4, and a 329-base pair deletion in exon 4 of the gene. [ 10 ]  The above mutations cause a  frameshift  in the gene. [ 10 ]  A frameshift mutation refers to a condition in which the reading frame of the gene is disrupted by the insertion or deletion of base pairs from the gene (if the number of inserted or deleted base pairs is not divisible by three). [ 11 ]  This frameshift mutation ultimately results in a premature  termination codon  (the formation of a termination codon at a position more "forward" than normal). [ 10 ]  Other mutations include a base pair transition in the  start codon , which is the starting site of translation of the gene. [ 10 ]  A transition mutation occurring at this codon disrupts the codon sequence and abolishes the site. [ 10 ]  This prevents the cell from carrying out translation of the gene.


The diagnosis of Filippi Syndrome is mostly done postnatally. [ 7 ]  Initial diagnosis of the disease relies on clinical observation of symptoms, including different degrees of syndactyly and craniofacial abnormalities, exhibited by affected individuals. [ 2 ] [ 3 ]  Diagnosis can also be done through  radiography , which checks for malformation of digits. [ 3 ]


Confirmation of diagnosis requires the use of genetic testing. [ 8 ]  Specifically, it can be done through detecting mutations in the CKAP2L gene, of which a total of eight causative variants having been identified. [ 8 ] [ 12 ]


Genetic testing of Filippi Syndrome makes use of three major techniques:


Currently, Filippi Syndrome has no direct cure. It is treated according to observed symptoms on affected individuals. [ 2 ]


Syndactyly exhibit varying degrees of severity in individuals. [ 1 ]  Hence not all affected individuals with this condition must undergo surgical intervention. [ 16 ]  For example, syndactyly that occurs at the  proximal  end of the digits may have limited effect on the normal functioning of the hand and foot, and correction through surgery is optional. [ 16 ]


Simple syndactyly is the condition of  cutaneous  fusion between two digits, and can be treated by surgically rebuilding the hourglass shape web space between digits. [ 17 ]  During surgery, incision is first carried out to separate the fused fingers. [ 16 ] [ 17 ]  It is followed by reconstruction of the web space's side walls using dorsal advancement flaps or  skin grafts  obtained from the affected individual's  groin . [ 16 ] [ 17 ]  After reconstruction, additional fingerpulp flaps are required for rebuilding of the  nailfold  between the  nail bed  and the surrounding skin if there is the occurrence of syndactyly at the tip of the fingers. [ 16 ] [ 17 ]


Treatment for complex syndactyly, which refers to the bony fusion between two digits, has a higher degree of complexity. It involves the reconstruction of web space as well as highly specific surgical procedures with accordance to different types of bony fusion. [ 17 ]  It may also require separation and relocation of the  flexor digitorum profundus  or tendon-diverted transplantation if the structure of the  tendons  in the fused digits are also affected by syndactyly. [ 17 ]


Professionals usually advice that affected individuals receive surgical treatment during the first two years of life to avoid hindrance to motor ability development. [ 16 ]


Craniofacial abnormalities can be corrected through surgical methods.


Affected individuals with severe hypertelorism may undergo  orbital osteotomy . [ 18 ]  The two major osteotomy methods are box osteotomy and facial bipartition, which operate from different osteotomy sites but follow the same general procedures. [ 19 ] [ 20 ]  During surgery, part of the bone, and sometimes excessive skin, are selectively removed from the central area of the nasofrontal region, such that this part of the skull can close in and correct hypertelorism. [ 19 ]  In addition,  bone grafts  are placed to provide support to the eyeballs and protect them from displacement. [ 19 ]


Underdeveloped nasal alae can be corrected by orofacial reconstruction. This procedure recreates the nasal alae with the use of  cartilage  grafts, which are cartilage taken from the patient's ear,  septum  or  rib . [ 21 ]  Afterwards, nasolabial flaps are placed to sustain the shape of the nose, specifically the alar groove. [ 21 ]


Patients who are affected by speech impairments can be treated by  speech therapy . [ 1 ]


Speech disability can be a manifestation of various physical or psychological causes. Symptomatic treatment of it is carried out after diagnostic tests such as video fluoroscopic barium study ("cookie swallow" test) or fiber-optic endoscopic evaluation. [ 22 ]  Despite the diversity in speech therapy techniques, most treatment plans follow the same progression: [ 23 ]


For post-treatment monitoring, computer-based speech therapy that makes use of instructional software can provide computer-led practices as aftercare and quantify performances outside of conventional treatments. [ 24 ]


Filippi syndrome is rare, with an estimated  prevalence  of less than one in a million. [ 7 ]  It has around thirty cases recorded in  medical literature . [ 2 ]


The number of affected males recorded is more than twice the number of affected females. [ 12 ]  However, this is insufficient to conclude that male are at a higher risk due to the small number of reported cases. [ 12 ]  However, the  CDC  says less than 25 cases have been reported, [ 25 ]  the  National Organization for Rare Disorders  says about 18 cases have been reported, [ 4 ]  while the  National Center for Advancing Translational Sciences  says 30 cases have been reported in literature. [ 26 ]


First arch syndromes  are  congenital defects  caused by a failure of  neural crest  cells to migrate into the  first pharyngeal arch . [ 1 ]   They can produce facial  anomalies .  Examples of first arch syndromes include  Treacher Collins syndrome  and  Pierre Robin syndrome .


Fleischer's syndrome  is an extremely rare  congenital  anomaly characterized by displacement of the  nipples , occasional  polymastia , and  hypoplasia  of both  kidneys . [ 1 ]


Genitoplasty  is  plastic surgery  to the genitals. Genitoplasties may be reconstructive to repair injuries, and damage arising from  cancer treatment , or congenital disorders, endocrine conditions, or they may be cosmetic. [ 1 ]


Genitoplasty surgery includes the following:


The grafts used in genitalplasty can be an  allogenic , an  autograft , a  xenograft , or an  autologous  material. [ 13 ]


Genital reconstruction surgery can correct  prolapse  of the  urinary bladder  into the vagina and protrusion of the rectum into the vagina. [ 2 ]  Female infants born with a  46,XX  genotype but have genitalia affected by  congenital adrenal hyperplasia  may undergo the surgical creation of a vagina. [ citation needed ]  Vaginoplasty is commonly used to treat women with the congenital absence of the vagina. [ 3 ]  Other reasons for the surgery are to treat adrenal hyperplasia, microphallus, Mayer-Rokitansky-Kustner disorder and for women who have had a vaginectomy after malignancy or trauma. Reconstructive and corrective vaginal surgery restores or creates the vagina. [ 11 ]


Surgeries to modify the cosmetic appearance of infants' and children's genitals  are controversial due to their  human rights implications . There is no clinical consensus about necessity, timing, indications or evaluation. [ 14 ]


Goldberg–Shprintzen syndrome  is a very rare connective tissue condition associated with mutations in  KIAA1279  gene which encodes KIF-binding protein (KBP), a protein that may interact with  microtubules  and  actin filaments . KBP may play a key role in cytoskeleton formation and  neurite  growth. [ 2 ] [ 3 ]


Hirschsprung's disease  may be part of the presentation. Developmental abnormalities shown by people with Goldberg–Shprintzen syndrome may be ocular, cardiac, urogenital, and skeletal. [ 3 ]


It was first observed by Sugarman and Vogel in 1981 and later established as a separate clinical identity by R B Goldberg and R J Shprintzen in 1982. The sibling pair had  microcephaly ,  hypertelorism , short stature,  submucosal   cleft palate , learning problems, and Hirschsprung aganglionic  megacolon  (HAM). This combination of symptoms had not been previously identified with a diagnosis. [ 3 ]


Three more cases were observed in 1988 by Hurst et al., although one of these cases could have been  Mowat-Wilson syndrome  instead of Goldberg–Shprintzen syndrome. [ 4 ]  Additional cases have since been documented sporadically across the world, although it remains extremely uncommon. [ 5 ] [ 6 ] [ 7 ] [ 8 ] [ 9 ]


Goldberg–Shprintzen syndrome presents a wide variety of phenotypic symptoms. It is characterized by a combination of any of the following symptoms:


Central nervous system: [ 10 ] [ 6 ] [ 2 ]


Cardiovascular: [ 3 ]


Gastrointestinal: [ 2 ] [ 5 ]


Optical: [ 2 ] [ 6 ]


Dysmorphic facial features: [ 2 ] [ 6 ] [ 10 ]


Anatomical abnormalities: [ 8 ] [ 2 ]


Additionally, while inconsistent, the following symptoms have been observed: [ 2 ]


Diagnosis is initiated by presentation of clinical features and confirmed by genetic testing. Symptoms can often be observed prenatally. Prenatal diagnosis is often used in families with a history of Goldberg–Shprintzen syndrome, as it is much more likely to occur. [ 11 ]  In particular,  polymicrogyria , microcephaly, and hypoplastic corpus callosum have been suggested as key clinical indicators of Goldberg–Shprintzen syndrome. [ 12 ]


There are numerous genetic tests available for Goldberg–Shprintzen syndrome. While some are only limited to testing for Goldberg–Shprintzen syndrome, a number of these genetic tests also test for  Marfan syndrome  and other syndromes closely related to Goldberg–Shprintzen syndrome. Others test for cleft lip/cleft palate, connective tissue disorders, or other symptoms that can be indicative of Goldberg–Shprintzen syndrome. [ 13 ]


Although Goldberg-Shprintzen syndrome cannot be cured, some of its symptoms can be managed. Cardiovascular complications present the greatest mortality risk to individuals with Goldberg-Shprintzen syndrome, so these are the priority for care and necessitate a cardiologist. Some cardiovascular conditions can only be monitored, while others can be treated with surgical intervention. Surgery can also be used to correct facial deformities, although surgery should be undertaken with great care to prevent the incidence of cardiac complications. Additionally, treatment by an ophthalmologist is also often necessary due to the high incidence of optical conditions associated with Goldberg-Shprintzen syndrome. Special education or support should also be provided to individuals affected by mental retardation. [ 3 ]


Goldberg-Shprintzen syndrome shows autosomal recessive inheritance patterns. [ 4 ]  The subjects studied for this disease included families which were highly consanguineous or inbred. Mutations of the  KIAA1279  gene were determined as a possible driving mutation causing the syndrome, and researchers found that the coding errors were caused by homozygous nonsense mutations or other homozygous truncating mutations. [ 7 ] [ 2 ]  The chromosomal location of the suspected gene associated with Goldberg-Shprintzen syndrome is located at a locus on 10q21.3-q22.1, which begins at the 21st position on the long arm of chromosome 10, although the determination of a definitively causative genetic mutation has not been agreed upon. [ 7 ]  The changes in the KIAA1279 gene are expected to cause problems in nervous system development due to a loss of functioning protein product. This is shown by the KIAA1279 gene's connection to both Hirschsprung's disease and bilateral generalized polymicrogyria, characteristics of Goldberg-Shprintzen syndrome. [ 7 ]


The prevalence of Goldberg-Shprintzen syndrome is scattered throughout the world, with cases recorded in France, Pakistan, Italy, Iraq, and multiple in Morocco. [ 4 ] [ 2 ] [ 7 ]  While it has appeared in a non-consanguineous family in one case, most cases present within consanguineous pedigrees which preserves the mutant allele that causes Goldberg–Shprintzen syndrome. [ 8 ]  Every case of Goldberg–Shprintzen syndrome is associated with a mutation in the same KIAA1279 gene.


Goldenhar syndrome  is a rare  congenital defect  characterized by incomplete development of the ear, nose,  soft palate , lip and  mandible  on usually one side of the body. Common clinical manifestations include  limbal dermoids , preauricular  skin tags  and  strabismus . [ 1 ]  It is associated with anomalous development of the  first branchial arch  and  second branchial arch . [ 2 ]


The term is sometimes used interchangeably with  hemifacial microsomia , although this definition is usually reserved for cases without internal organ and vertebrae disruption.


It affects between 1 in 3,500 and 1 in 5,600 live births, with a male-to-female ratio of 3:2. [ 3 ]


Chief markers of Goldenhar syndrome are incomplete development of the ear, nose,  soft palate , lip, and  mandible  on usually one side of the body. Additionally, some patients will have growing issues with internal organs, especially heart, kidneys and lungs. Typically, the organ will either not be present on one side or will be underdeveloped. While it is more usual for there to be problems on only one side, it has been known for defects to occur bilaterally (approximate incidence 10% of confirmed GS cases). [ citation needed ]


Other problems can include severe  scoliosis  (twisting of the vertebrae),  limbal dermoids  and  hearing loss  (see  hearing loss with craniofacial syndromes ), and deafness or blindness in one or both ears/eyes.  Granulosa cell tumors  may be associated as well. [ citation needed ]


The cause of Goldenhar syndrome is largely unknown. However, it is thought to be multifactorial, although there may be a genetic component, which would account for certain familial patterns. It has been suggested that there is a branchial arch development issue late in the first trimester. [ citation needed ]


An increase in Goldenhar syndrome in the children of  Gulf War  veterans has been suggested, but the difference was shown to be statistically insignificant. [ 4 ]


No general consensus on the minimal diagnostic criteria exists. [ 5 ]  The syndrome is characterized by hemifacial microsomia due to underdevelopment of structures derived from the  1st and 2nd branchial arches such as eyes, ears, palate, mandible. However, the presentation of the syndrome is highly variable. [ 6 ]  Some of its features may include: [ 6 ]


Treatment is usually confined to such surgical intervention as may be necessary to help the child to develop e.g. jaw distraction/bone grafts, ocular dermoid debulking (see below), repairing cleft palate/lip, repairing heart malformations or spinal surgery. Some patients with Goldenhar syndrome will require assistance as they grow by means of  hearing aids  or glasses. Stem cell grafting (womb tissue grafting) has been successfully used to "reprogram" eye dermoids, effectively halting the regrowth of eye dermoids. These tissues that grow on the eye are "mis-programmed" cells (sometimes tooth or nail cells instead of eye cells). [ citation needed ]


Prevalence ranges from 1 in 3,500 to 8,500 births. [ 7 ]


The condition was documented in 1952 by Belgian–American ophthalmologist  Maurice Goldenhar  (1924–2001). [ 8 ] [ 9 ]


Antonietta (Tognina) Gonsalvus , also  Gonzalves  or  Conzales  (born around 1572–1580 in France) was a so-called  monkey girl . She became famous for suffering (like her father and three of her five brothers) from  hypertrichosis  (a  congenital disease ). Her family is considered to be the oldest case of human excessive hair growth described in Europe. [ 1 ]  Antonietta's death year is not known but she supposedly died in  Capodimonte  (Viterbo), Italy, where her father also died.


Antonietta has been depicted in various paintings and prints both as a little girl and as a young woman and has become known under the name  Tognina . She grew up in  Fontainebleau  and was part of the court of King  Henry II of France  and his wife,  Catherine de Medici  de Valois. Tognina is mentioned primarily in reports about her family, some of whom like her, suffered from hypertrichosis, also called  Ambras syndrome . [ 2 ]


Tognina's father,  Petrus Gonsalvus , was born in  Tenerife , Canary Islands, in 1556. As a child, he was sent to the court of Henry II where he was initially kept as a monkey and didn't receive attention as a human until he grew up. Petrus, who was eventually educated and learned to speak  Latin , married a beautiful woman, Catherine Raffelin from Paris who did not have abnormal body hair. [ 1 ] [ 3 ] [ 4 ]


The couple had several children, some of whom, including Tognina, inherited their father's illness and others who did not. King Henry gave the Gonsalvus family a part of the vast park at his  Palace of Fontainebleau  to give them a natural environment and protection. Petrus, called the "ape-man," regularly participated in social events, dressed in courtly robes, while little Tognina always dressed like a doll. [ 2 ]  The Gonsalvus family is known to have traveled to Italy around 1580–1590 as their stay was recorded at the court of  Margaret of Parma . [ 1 ]


The family's excessive hairiness attracted the interest of scholars. The Italian doctor and naturalist  Ulisse Aldrovandi  (1522–1605) reported in detail about the family in his book,  Monstrorum Historia , published in 1642, and mentioned Ambras in  Tyrol  as their place of residence. In the local castle,  Archduke Ferdinand II  of Tyrol and Rudolf II had set up an art and curiosity chamber that included a huge collection of curiosities, which also housed a painting of the Gonsalvus family, made by Rudolf II's court painter, the  Antwerp  miniaturist  Georg Hoefnagel . That painter mentioned the family as a special "species of animal" in a sketchbook for the  Animalia Rationalia et Insecta . [ 2 ]


Italian painter  Lavinia Fontana [ 3 ]  made a famous portrait of little Tognina holding a letter that tells the story of the child's family.


"Don Pietro, a savage discovered on the Canary Islands, was shipped to his Serene Highness Henri King of France and from there to his Excellency the Duke of Parma. I, Antonietta, was born from him and today I can be found at the Court of Dame  Isabella Pallavicina , the Honorable Marquise of  Soragna .” [ 3 ]


In 2016, Tognina's portrait was used in a horror video game called  Layers of Fear  and represents a character nicknamed ‘Babyface.’ [ 1 ]


Guizar-Vasquez-Sanchez-Manzano syndrome  is an extremely rare  genetic  and  congenital  disorder that is characterized by facial dysmorphisms (more specifically, chubby cheeks, mild frontal bossing, a beaked nose with an accompanying low nasal bridge, malar hypoplasia, peculiar philtrums and upper lips),  pectus carinatum , and  joint hypermobility . Only 2 cases have ever been reported in medical literature, with both of those cases coming from siblings of the same family. [ 2 ] [ 3 ] [ 4 ]


Hajdu–Cheney syndrome , also called  acroosteolysis with osteoporosis and changes in skull and mandible ,  arthrodentoosteodysplasia  and  Cheney syndrome , [ 1 ]  is an extremely rare  autosomal   dominant   congenital disorder [ 2 ] [ 3 ]  of the  connective tissue  characterized by severe and excessive  bone resorption  leading to  osteoporosis  and a wide range of other possible symptoms. Mutations in the  NOTCH2  gene, identified in 2011, cause HCS. HCS is so rare that only about 50 cases have been reported worldwide since the discovery of the syndrome in 1948 [ 4 ]


Hajdu–Cheney syndrome causes many issues with an individual's connective tissues. Some general characteristics of an individual with Hajdu–Cheney syndrome include bone flexibility and deformities, short stature, delayed  acquisition of speech  and  motor skills ,  dolichocephalic  skull,  Wormian bone , small maxilla, hypoplastic frontal sinuses, basilar impression, joint laxity, bulbous finger tips and severe osteoporosis. Wormian bone occurs when extra bones appear between cranial sutures. Fetuses with Hajdu–Cheney syndrome often will not be seen to unclench their hands on obstetrical ultrasound. They may also have low-set ears and their eyes may be farther apart than on a usual child, called  hypertelorism . Children's heads can have some deformities in their shape and size ( plagiocephaly ). Early tooth loss and bone deformities, such as serpentine tibiae and fibulae, are also common in those affected. [ citation needed ]


Hajdu–Cheney syndrome is a monogenic disorder. The disorder is inherited and controlled by a single pair of genes. A single copy of the mutant gene on an autosome causes HCS. HCS is an autosomal dominant disorder, only one parent with the defective gene is needed to pass the disorder to the offspring. [ citation needed ]


Mutations within the last coding exon of  NOTCH2  that remove the  PEST  domain and escape the  nonsense-mediated mRNA decay  have been shown to be the main cause of Hajdu–Cheney syndrome. [ 5 ] [ 6 ] [ 7 ]  The NOTCH2 gene plays a very important role in skeletogenesis. Mutations of NOTCH2 that seem to cause HCS occur in the last coding exon of the gene (exon 34). These mutations remove PEST domains, which mediate proteosomal destruction of the protein. These PEST domains are removed due to the premature stop codon in the amino acid sequence. All HCS alleles are observed to have premature protein destruction before the PEST sequence is fully translated. The result is a mature  NOTCH2  gene with a partially completed PEST sequence. In some cases, no PEST sequence at all is seen. This leads to the no proteosomal destruction of the protein. [ citation needed ]


The  NOTCH2  gene is ubiquitously expressed in all embryonic tissue. When researching HCS in mice, the homozygous deletion of  NOTCH2  leads to death. This observation is important because it explains how the HCS phenotype is not isolated to only one system of the body.  NOTCH2  is also shown to regulate RANK-L osteoclastogenesis, which is the production of functional osteoclasts. Osteoclasts are the component that breaks bone down. This is why bone loss is observed in HCS patients, due to the overactivation of RANK-L. [ citation needed ]


The mechanism thought to cause HCS is an abnormality in osteoblast and osteoid function. These are major components of bone development, and the low function of each leads to the weak bones that characterize HCS. [ citation needed ]


One of the main methods of pinpointing a  NOTCH2  mutation that leads to HCS is through whole genome sequencing. This is then followed by exome capture by means of in-solution hybridization. The exome part of the genome consists of exons. Parallel sequencing follows the hybridization, which results in about 3.5 Gb of sequence data. These sequence data are then analyzed. Through sequence analysis and symptom presentation in HCS patients, this proves to be the most definitive method of diagnosis. [ citation needed ]


Laboratory testing reveals multiple mutations of HCS. Two genetic variants result in sporadic HCS symptoms, which are HCS-02 and HCS-03. These mutations produce symptoms that come and go, but have been present  de novo . HCS-03 was identified as the variant that is passed through affected family members and presents symptoms throughout the lifetime of the individual. All variants of HCS lead to the same premature termination of PEST sequences which compromise normal function of  NOTCH2 .  NOTCH  has four different receptors, which have an affinity for similar ligands. They are classified as single-pass transmembrane receptors. [ citation needed ]


Since about 2002, some patients with this disorder have been offered drug therapy with  bisphosphonates  (a class of osteoporosis drugs) to treat problems with bone resorption associated with the bone breakdown and skeletal malformations that characterize this disorder. Brand names include Actonel (risedronate/alendronate), made by Merck Pharmaceuticals. Other drugs include Pamidronate, made by Novartis and Strontium Ranelate, made by Eli Lilly. However, for more progressive cases, surgery and bone grafting are necessary. [ citation needed ]


It is named after Nicholas Hajdu (1908–1987), a Hungarian-English radiologist working in the UK and William D. Cheney, MD (1899–1985), a US radiologist. [ citation needed ]


Halal syndrome  is a rare disorder characterised by  microcephaly ,  cleft palate , and variable other anomalies. The disease is named after Fahed Halal, one of its discoverers.


Halperin-Birk syndrome (HLBKS)  is a rare autosomal recessive neurodevelopmental disorder caused by a null mutation in the  SEC31A  gene. Signs and symptoms include intrauterine growth retardation, marked developmental delay, spastic quadriplegia with profound contractures, dysmorphism, and optic nerve atrophy with no eye fixation. Brain MRI demonstrated microcephaly and agenesis of the  corpus callosum . [ 1 ]


The syndrome was first described in 2019 by Dr. Daniel Halperin and Prof.  Ohad Birk  at the Morris Kahn Laboratory for Human Genetics,  Ben Gurion University of the Negev . [ citation needed ]


Source: [ 1 ]


Halperin-Birk syndrome describes a severe autosomal recessive neurodevelopmental disorder caused by a loss of function mutation in  SEC31A , a component of the coat protein complex II ( COP-II ).  SEC31A  (transcript variant 1; NM_ 001318120), also known as KIAA0905 and SEC31-related protein A (SEC31L1), encodes the transport protein SEC31A, a 1220 amino acid protein that is highly conserved through evolution. It contains multiple  WD repeats  near the N-terminus and conserved proline-rich region in its C-terminal. [ 2 ]  SEC31A is a component of the  COPII  protein complex, responsible for vesicle budding from the  Endoplasmic Reticulum  (ER). It has been demonstrated to be highly expressed in the  notochord ,  optic tectum ,  otic vesicle ,  cleithrum , and fin during  embryogenesis . [ 3 ]  Its importance to neuronal and craniofacial development has been demonstrated mainly through its efficient coupling with  SEC13  and the SEC23-SEC31A interface. Failure to recruit SEC31A results in severe secretion defects of  procollagen , and an enlarged ER, in line with aberrant protein secretion. [ citation needed ]


The  COP-II complex  comprises five highly conserved proteins, among these  SEC31A , creating small membrane vesicles that originate from the ER. [ 4 ] [ 5 ]  Budding of these vesicles is essential in the cellular trafficking pathway, through which membrane and luminal cargo proteins are transported from their site of synthesis to other cellular compartments. [ 6 ]  This machinery assembles hierarchically, driven by the initial recruitment and activation of the small  GTPase   SAR1 , which exists in a soluble cytoplasmic form when in its  GDP -bound state. [ 7 ]  SAR1 is promoted by  SEC12 , a membrane-bound  GEF  that catalyzes  GDP / GTP  exchange. [ 8 ]  Once tightly anchored into the ER membrane, the active GTP-bound SAR1 recruits the  SEC23 - SEC24  heterodimer to form the inner "pre-budding" complex, capable of engaging cargo through interactions between SEC24 and multiple ER export motifs. [ 9 ] [ 10 ]  Finally, the  SEC13 –SEC31A hetero-tetramer is recruited to promote coat polymerization, membrane curvature, and eventually membrane fission. [ 11 ] [ 12 ]  With the full complement of the COP-II complex, the extruded membrane is separated from the ER membrane to form an intact vesicle. [ 13 ]


Most mammalian COP-II complex subunits have one or more paralogues with partially redundant functions, as the loss of selected copies often results in a genetic disease. [ 14 ]  The mammalian repertoire consists of two SAR1 paralogs,  SAR1A  and  SAR1B ; two SEC23 paralogs,  SEC23A  and  SEC23B ; four SEC24 paralogs,  SEC24A ,  SEC24B ,  SEC24C , and  SEC24D ; a single SEC13 and two SEC31 paralogs: SEC31A, comprising part of the SEC13/SEC31 hetero-tetramer, and SEC31B. The repertoire of COP-II paralogs available in mammals could contribute to a wide variety of COP-II coats, thus facilitating selective cargo transport in a tissue-specific manner. Alternative splicing could further contribute to the COP-II vesicle and cargo selection diversity. [ 15 ]


CRISPR/Cas9 -mediated knockdown of the  SEC31A  gene in human  SH-SY5Y neuroblastoma  cells resulted in the failure of the cells to expand to generate viable clones. In addition, knockdown of the gene in  HEK293  cells increased susceptibility to  ER stress  compared to controls. These results suggest that enhanced ER stress response is likely part of the molecular mechanism of the human disease. [ 1 ]


There is no specific test to diagnose HLBKS other than exome/genome sequencing. [ 1 ]


Currently, there are no genetic therapies specifically targeting the underlying cause of HLBKS. However, following the identification of the syndrome, a  preimplantation genetic diagnosis  (PGD) can be offered when one or both genetic parents are carriers of a mutation in this gene. [ 1 ]


In-vivo  C. elegans  experiments have demonstrated that  SEC31A -deficient mutants are embryonically lethal due to various developmental defects. [ 16 ]  Halperin et al. (2019) found that complete loss of  Sec31a  in  Drosophila  was embryonically lethal and associated with eye and brain development defects, consistent with abnormal neurodevelopment. [ 1 ]


Hearing loss with craniofacial syndromes  is a common occurrence. Many of these multianomaly disorders involve structural malformations of the  outer  or  middle ear , making a significant  hearing loss  highly likely.


Individuals with Treacher Collins syndrome often have both  cleft palate  and hearing loss, in addition to other disabilities. Hearing loss is often secondary to absent, small or unusually formed ears ( microtia ) and commonly results from malformations of the  middle ear . Researchers have found that most patients with Treacher Collins syndrome have symmetric  external ear  canal abnormalities and symmetrically dysmorphic or absent  ossicles  in the  middle ear  space.  Inner ear  structure is largely normal. Most patients show a moderate  hearing impairment  or greater, and the type of loss is generally a  conductive hearing loss . Patients with Treacher Collins syndrome exhibit hearing losses similar to those of patients with malformed or missing ossicles (Pron  et al. , 1993).


Persons with Pierre Robin sequence (PRS) are at greater risk for hearing impairment than persons with cleft lip and/or palate without PRS. One study showed an average of 83% hearing loss in PRS, compared to 60% in cleft individuals without PRS (Handzic  et al. , 1995). Similarly, PRS individuals typically exhibit conductive, bilateral hearing losses that are greater in degree than in cleft individuals without PRS. Middle ear effusion is generally apparent, with no middle ear or inner ear malformations. Accordingly, management by  ear tubes  ( myringotomy  tubes) is often effective and may restore normal levels of hearing (Handzic  et al. , 1995).


The hearing loss most typical in patients with Stickler syndrome is a  sensorineural hearing loss , indicating that the source of the deficit lies in the  inner ear , the  vestibulocochlear nerve  or the processing centers of the brain. Szymko-Bennett  et al.  (2001) found that the overall hearing loss in Type   I Stickler Syndrome is generally mild and is not significantly progressive. Hearing loss is more common in the higher frequencies, from about 4000–8000 Hz (Szymko-Bennett  et al. , 2001). This mildly progressive sensorineural loss, or more significant losses (associated with Types   II and III Stickler syndrome) is present in about 80% of patients with Stickler syndrome. However, other patients are also susceptible to conductive losses, similar to nonsyndromic cleft patients (Peterson-Falzone  et al. , 2001).


Patients with  Apert syndrome  have a high occurrence of middle ear disease,  otitis media  and  conductive hearing loss  (Perterson-Fazone  et al. , 2001). Conductive hearing loss is frequently seen in this population due to almost constant middle ear disease (Gould  et al. , 1982). Furthermore, inner ear anomalies have been described in  Apert syndrome , such as dilatation of the  vestibule , dysplastic  semicircular canals  and  cochlear  malformations (Zhou G et al. Otol Neurotol. 2009 Feb;30(2):184-9)


Patients with Crouzon syndrome sometimes exhibit malformations of the external ear and/or the middle ear, such as malalignment of the  pinna  (Peterson-Falzone  et al. , 2001). Literature has suggested that persons with Crouzon syndrome typically have  conductive hearing loss  caused by middle ear effusion (or fluid in the middle ear) and perforation to ossicular fixation ( ossicles ), intratympanic bony masses ( tympanic membrane ), ossicular anomalies and closure of the  oval window . Patients with a  sensorineural hearing loss  have also been reported but are less likely to occur.


A  conductive hearing loss  along with middle ear disease is most commonly seen in patients with Pfeiffer syndrome; although, there have been reports of mixed hearing loss as well. The hearing loss is most typically caused by stenosis or  atresia  of the  auditory canal , middle ear  hypoplasia  and ossicular hypoplasia (Vallino-Napoli, 1996).


Conductive hearing loss  has been reported by many with ectrodactyly–ectodermal dysplasia–cleft (EEC) syndrome in association with a  cleft palate  (Perterson-Falzone, 2001).


In Saethre–Chotzen syndrome, the ears may be low set, posteriorly rotated, have other minor anomalies and there may be a presence of a  conductive hearing loss  or a mixed hearing loss (Perterson-Falszone, 2001). Hearing loss in this group can also be caused by middle ear disease when a cleft palate is present. [ 1 ]


About 70% of individuals with velocardiofacial syndrome (VCFS) have minor auricular malformations, or malformations of the ear. In this syndrome, the ears are typically low-set and somewhat posteriorly rotated. In addition to external malformations, individuals with VCFS are more vulnerable to  otitis media  because of the presence of a cleft or other form of  velopharyngeal inadequacy . The hearing loss associated with VCFS is conductive when otitis media is present (Peterson-Falzone  et al. , 2001). There are also sporadic reports of  sensorineural hearing loss  and a mixed hearing loss. Of individuals with VCFS who have a hearing loss, only 11% had a sensorineural loss and 5% a mixed loss (Reyes  et al. , 1999).


Individuals with hemifacial microsomia, also called oculoauriculo-vertebral spectrum, often have ear malformations. These malformations can be in the form of preauricular ear pits, complete absence of the auricle, stenosis or atresia of the external auditory canal, ossicular malformations, middle ear deformities, and incomplete pneumatization of the temporal bone. Rahbar  et al.  (2001) found that 95% of individuals with this syndrome have an ear malformation of some type. In addition to ear malformations, a  conductive hearing loss  can be present, typically ranging from mild to severe. There are also reported cases of  cochlear  involvement and  sensorineural hearing loss . Rahbar  et al.  (2001) found that 86% of patients with Hemifacial Microsomia have a conductive hearing loss and 10% have a sensorineural hearing loss. There is no correlation between the severity of dysmorphic features and the degree of hearing loss, meaning individuals with mild malformations can have severely impaired hearing.


Individuals with Nager syndrome typically have the malformations of the auricle, external auditory canal and middle ear, including the  ossicles . These malformations were found in 80% of individuals with Nager syndrome. Inner ear malformations, however, are not typically seen in this population. Middle ear disease is common among individuals with Nager syndrome. Chronic  otitis media  and  Eustachian tube  deformity can result in  conductive hearing loss . For this reason, early detection and treatment for middle ear disease is crucial in this population. Sensorineural hearing loss is not a typical characteristic of Nager syndrome; however, a subset of individuals present with a mixed hearing loss, due to a progressive sensorineural component combined with the typical conductive hearing loss (Herrman  et al. , 2005).


Hemifacial hypertrophy  (also termed  facial hemihypertrophy , [ 2 ]   facial hemihyperplasia , [ 2 ]  or  Friedreich's disease ) [ 3 ]  abbreviated as  ( HFH ) is rare  congenital disease  characterized by unilateral enlargement of the  head  and  teeth . [ 4 ] [ 5 ]   It is classified as true HFH (THFH) with unilateral enlargement of the  viscerocranium , and partial HFH (PHFH) in which not all structures are enlarged. Hemifacial hypertrophy can cause a wide spectrum of defects or may involve only  muscle  or  bone . [ 5 ]  it is usually treated surgically. [ 6 ]   It is believed to be a minor form of  hemihypertrophy . [ 7 ]


Hemifacial microsomia  ( HFM ) is a  congenital disorder  that affects the development of the lower half of the face, most commonly the ears, the mouth and the  mandible . It usually occurs on one side of the face, but both sides are sometimes affected. If severe, it may result in difficulties in breathing due to obstruction of the  trachea —sometimes even requiring a  tracheotomy . With an incidence in the range of 1:3500 to 1:4500, it is the second most common birth defect of the face, after  cleft lip and cleft palate . [1]  HFM shares many similarities with  Treacher Collins syndrome .


The clinical presentation of HFM is quite variable. The severity may depend on the extent of the area with an insufficient blood supply  in utero , and the gestational age of the fetus at which this occurs. In some people, the only physical manifestation may be a small and  underdeveloped external ear . In more severe cases, multiple parts of the face may be affected. Some people with HFM may have  sensorineural hearing loss  and decreased visual acuity or even blindness. [ citation needed ]


It can be thought of as a particularly severe form of HFM, in which extracranial anomalies are present to some extent. Some of the internal organs (especially the heart, kidneys, and lungs) may be underdeveloped, or in some cases even absent altogether. The affected organs are typically on the same side as the affected facial features, but bilateral involvement occurs in approximately 10% of cases. Deformities of the vertebral column such as scoliosis may also be observed.  [ citation needed ]


While there is no universally accepted grading scale, the OMENS scale (standing for Orbital, Mandible, Ear, Nerves and Soft tissue) was developed to help describe the heterogeneous  phenotype  that makes up this  sequence  or  syndrome . [ citation needed ]


Intellectual disability  is not typically seen in people with HFM. [ citation needed ]  Hemifacial microsomia sometimes results in  temporomandibular joint disorders . [ 1 ]


The condition develops in the  fetus  at approximately 4 weeks'  gestational age , when some form of vascular problem such as  blood clotting  leads to  insufficient blood supply  to the face. This can be caused by physical trauma, though there is some evidence of it being  hereditary   [2] .  This restricts the developmental ability of that area of the face. Currently there are no definitive reasons for the development of the condition. [ citation needed ]


Figueroa and Pruzanksky classified HFM patients into three different types: [ 2 ]


Depending upon the treatment required, it is sometimes most appropriate to wait until later in life for a surgical remedy – the childhood growth of the face may highlight or increase the symptoms.  When surgery is required, particularly when there is a severe disfiguration of the jaw, it is common to use a rib graft to help correct the shape. [ citation needed ]


According to literature, HFM patients can be treated with various treatment options such as functional therapy with an appliance,  distraction osteogenesis , or costochondral graft. The treatment is based on the type of severity for these patients. According to Pruzanksky's classification, if the patient has moderate to severe symptoms, then surgery is preferred. If patient has mild symptoms, then a functional appliance is generally used. [ 3 ]


According to Dr. Harry Pepe, a pediatrician from  Hollywood, Florida , the goal of treatment in hemifacial microsomia is to elongate the deficient jaw bone to restore facial symmetry and correct the slanting bite (occlusion). [ 4 ]


Patients can also benefit from a  Bone Anchored Hearing Aid  (BAHA).


The condition is also known by various other names: [ citation needed ]


In  medicine ,  heterotopia  is the presence of a particular tissue type at a non-physiological site, but usually co-existing with original tissue in its correct anatomical location. In other words, it implies  ectopic  tissue, in addition to retention of the original tissue type.


In neuropathology, for example,  gray matter heterotopia  is the presence of  gray matter  within the  cerebral white matter  or  ventricles . Heterotopia within the brain is often divided into three groups: subependymal heterotopia, focal cortical heterotopia and band heterotopia. Another example is a  Meckel's diverticulum , which may contain heterotopic gastric or pancreatic tissue.


In  biology  specifically,  heterotopy  refers to an altered location of trait expression. [ 1 ]  In her book  Developmental Plasticity and Evolution , Mary-Jane West Eberhard has a cover art of the  sulphur crested cockatoo  and comments on the back cover "Did it's [ sic ] long crest[head] feathers evolve by gradual modification of ancestral head feathers? Or are they descendants of wing feathers, developmentally transplanted onto the head". This idea sets the tone for the rest of her book which goes into depth about developmental novelties and their relation to evolution. Heterotopy is a somewhat obscure but well demonstrated example of how developmental change can lead to novel forms. The central concept is that a feature seen in one area of an organism has had its location changed in evolutionary lineages.


Heterotopy in molecular biology is the name given to the expression or placement of a gene product from what is typically found in one area to another area. It can also be further expanded to a subtle form of  exaptation  where a gene product used for one underlying purpose in a diverse group of organisms can re-emerge repeatedly to produce seemingly  paraphyletic  distributions of traits. But actual phylogenetic analysis supports a monophyletic model as does evolutionary theory. Heterotopy is used to explain this and there are so commonly cited examples.


An example is  chitin  a very durable structural protein used in surgical [ 2 ]  sutures as well as durable  varnishes  but is common to many animals especially  crustaceans  and  insects . But is also found in the  African clawed frog  ( Xenopus laevis ). [ 3 ]


Wagner et al., suggest that chitin might have a microscopic function observed in cell to cell signaling and the manufacture of insect cuticle for example might represent a recurrent change in the location of expression  chitin
Speculative, but however Chitin synthase is maintained in many lineages where it does not have an obvious macroscopic function. [ 4 ]


It is thought that because so many organisms share such a profound degree of genetic and molecular similarity that shifts in the location of expression might be a regular occurrence throughout time.


Molecular analysis shows that proteins that seem to have a single specific function are instead found in many different tissue types.  One example of this phenomenon is crystallin, a clear protein that makes up the lens of the eye; it is also has structural functions in the heart.


Ho–Kaufman–Mcalister syndrome  is a rare  congenital malformation  syndrome where infants are born with a  cleft palate ,  micrognathia ,  Wormian bones ,  congenital heart disease , dislocated  hips , bowed  fibulae , preaxial  polydactyly  of the feet, abnormal skin patterns, and most prominently, missing  tibia . The  etiology  is unknown. Ho–Kaufman–Mcalister syndrome is named after  Chen-Kung Ho ,  R.L. Kaufman , and  W.H. Mcalister  who first described the syndrome in 1975 at  Washington University in St. Louis . It is considered a  rare disease  by the  Office of Rare Diseases  (ORD) of the  National Institutes of Health  (NIH).


Ho–Kaufman–Mcalister Syndrome Summary at PubMed


Ho CK, Kaufman RL, Mcalister WH (1975). "Congenital Malformations: Cleft Palate, Congenital Heart Disease, Absent Tibiae, and Polydactyly."  American Journal of Diseases of Children  1975 Jun. 129(6):714–6.


Holt–Oram syndrome  (also called  atrio-digital syndrome, atriodigital dysplasia, cardiac-limb syndrome, heart-hand syndrome type 1, HOS, ventriculo-radial syndrome ) is an  autosomal dominant disorder  that affects  bones  in the  arms  and  hands  (the upper limbs) and often causes  heart  problems. [ 1 ]  The syndrome may include an absent  radial bone  in the forearm, an  atrial septal defect  in the heart, or heart block. [ 2 ]  It affects approximately 1 in 100,000 people. [ 2 ]


All people with Holt-Oram syndrome have at least one abnormal  wrist bone , which can often only be detected by  X-ray . [ 1 ]  Other bone abnormalities are associated with the syndrome. These vary widely in severity, and include a missing thumb, a thumb that  looks like a finger ,  upper arm bones  of unequal length or underdeveloped, partial or complete absence of bones in the forearm, and abnormalities in the  collar bone   or  shoulder blade . [ 1 ] [ 2 ]  Bone abnormalities may affect only one side of the body or both sides; if both sides are affected differently, the left side is usually affected more severely. [ 1 ]


About 75 percent of individuals with Holt–Oram syndrome also have congenital heart problems, [ 2 ]  with the most common being defects in the tissue wall between the upper chambers of the heart ( atrial septal defect ) or the lower chambers of the heart ( ventricular septal defect ). [ 3 ]  People with Holt–Oram syndrome may also have abnormalities in the  electrical system that coordinates contractions of the heart chambers . [ 1 ]  Cardiac conduction disease can lead to slow heart rate ( bradycardia ); rapid, ineffective contraction of the heart muscles ( fibrillation ); and  heart block . [ 1 ] [ 2 ]  People with Holt-Oram syndrome may have only congenital heart defects, only cardiac conduction disease, both or neither. [ 1 ] [ 2 ]


Mutations in the  TBX5  gene cause Holt–Oram syndrome. [ 1 ]  The  TBX5  gene  produces a protein that is critical for the proper development of the heart and upper limbs before birth. [ 1 ]


Holt–Oram syndrome has an  autosomal dominant  pattern of inheritance, meaning one abnormal copy of the gene is sufficient to cause disease, which each child has a 50% chance of inheriting from an affected parent. [ 1 ]  However, in 85 percent of cases, the gene mutation isn't inherited, but a new  mutation . [ 2 ]


Diagnosis may be made on physical features alone, if a person has an arm or hand bone abnormality and a personal or family history of heart problems. [ 2 ]  If the symptoms aren't enough to diagnose, a person may undergo  genetic testing  for the mutations associated with the syndrome. [ 2 ]


A person with Holt-Oram syndrome may need various treatments, depending on how the syndrome manifests. Surgery, prosthetics and physical or occupational therapy can help people with bone abnormalities. [ 2 ]  Heart defects may call for surgery, medication, pacemakers or close monitoring. [ 2 ]  Pregnant women with Holt-Oram syndrome and heart abnormalities should be followed by a cardiologist during pregnancy. [ 2 ]


It is named for Mary Holt and Samuel Oram, who published a paper on it in 1960. [ 4 ] [ 5 ]


Hydrolethalus syndrome  ( HLS ) is a rare  genetic disorder  that causes improper  fetal development , resulting in  birth defects  and, most commonly,  stillbirth . [ 1 ]


HLS is associated with  HYLS1  mutations. The gene encoding HYLS1 is responsible for proper cilial development within the human body.  Cilia  are microscopic projections that allow sensory input and signalling output within cells, as well as cell motility. [ 2 ]  Dysfunction results in a range of abnormalities that are often the result of improper cell signalling. [ 3 ]  A variant form, HLS2, with additional mutations to the  KIF7  gene, is less common. [ 4 ]   KIF7  also ensures correct cilia formation and function, specifically cilia stability and length. [ 5 ]


Hydrolethalus syndrome (HLS) was first mistakenly identified in Finland, during a study on  Meckel syndrome . [ 6 ]  Like HLS, Meckel syndrome presents with severe physiological abnormalities, namely disruptions to the  central nervous system  and the presence of extra fingers or toes ( polydactyly ). [ 6 ]  HLS can be distinguished from Meckel syndrome by analysing kidney function, which is dysfunctional in Meckel syndrome as a result of  cyst  formation. [ 7 ]


HLS presents itself as various, lethal developmental abnormalities, which often result in either premature stillbirth or death shortly after birth. [ 6 ]  Rare cases of children born with HLS surviving for several months have been noted. [ 7 ]  A characteristic abnormality of HLS is an absence of brain tissue and midline structures, with the presence of excess brain fluid ( hydrocephalus ) as a result of abnormal development of the central nervous system. [ 6 ]  Other common defects include incomplete lung development, heart defects, a  cleft lip  or  palate , polydactyly, and an abnormally small jaw. [ 6 ]  Stillbirth and an excess of amniotic fluid ( polyhydramnios ) are common during pregnancy with a HLS-affected foetus, with cases of up to 8 litres cited compared to the normal 1 litre. [ 7 ]  Less common symptoms such as abnormally small eyes and a broad nose are also possible. [ citation needed ]


HLS is caused by a genetic  missense mutation  of the  HYLS1  gene, encoding for Hydrolethalus syndrome protein 1, on  chromosome 11 ; [ 7 ]  a single base change to the  amino acid  sequence for  HYLS1  in  exon  6 involves the replacement of  aspartic acid  211 with  glycine  (D211G) in the polypeptide chain. [ 8 ]  Exon 6 is the only protein coding exon in  HYLS1 ; proper functioning of exons 1-5 ensures regulation and expression of the entire protein. [ 7 ]
HLS is an  autosomal recessive  syndrome; [ 9 ]  development is only possible if both parents carry the defective gene, and in that instance, the risk of the foetus developing the syndrome is 25%. HLS is a member of the  Finnish disease heritage , [ 7 ]  with incidences more common in Finland than the rest of the world; roughly 1 in 20,000 developing foetuses are affected in Finland. [ 6 ]  Rare cases in other regions have also been documented, often with less severe  phenotypes  as a result of  allele  variability across countries, allowing survival of affected offspring for up to several months. [ 7 ]  Individuals of Finnish descent are advised to undergo  genetic testing  before attempting to conceive. [ citation needed ]


Prior to the discovery of HLS, the  HYLS1  gene was unknown, and similar genes within humans have not been identified. [ 7 ]   Orthologs , genes in other species with common ancestral heritage, have been examined to explain the pathophysiology of HLS; a similar gene within the roundworm,  Caenorhabditis elegans , is responsible for the formation of cilia. [ 10 ]  Current hypotheses place a dysfunction of cilia as the main cause of HLS defects arising from the  HYLS1  mutation in humans. [ 7 ] [ 9 ]
Differences between  wild type  and mutant  HYLS1  have been clearly observed; the wild type form is localised to the  cytoplasm , while the mutant form is localised to the  nucleus  and forms small clusters, suggesting that the mutant gene disrupts cellular localisation. [ 9 ]  The protein encoded by the  HYLS1  mutant form is unable to carry out essential targeting of  centrioles  to the plasma membrane, disrupting ciliary function, which results in  ciliopathy . [ 10 ]  As cilia are located in almost all cells throughout the body, cilial dysfunction causes developmental defects in a range of organs and thus the phenotype of HLS can vary greatly, though brain malformation and polydactyly are most commonly observed. [ citation needed ]


Currently, no  environmental factors  are known to increase the likelihood of HLS development or progression; HLS is caused only by  genetic abnormalities . [ 5 ]


The  pathophysiology  of HLS is abnormal cilia development arising from the inability of the mutated  HYLS1  gene to correctly target centrioles to the plasma membrane. [ 10 ]  Specifically, transition fibres within the transition zone, at the base of the  axoneme  and adjoining to the plasma membrane, lack proper development. [ 11 ]  As these structures form the cilial gate, improper development results in a loss of selectivity for protein entry into the ciliary compartment. [ 5 ]


Mutations in  KIF7  have also been noted in patients that present a similar phenotype to HLS and the characteristic  HYLS1  A to G transformation;  homozygous  deletion of the  KIF7  gene causes a variant form of HLS, HLS2. [ 4 ]   KIF7  encodes a structural factor vital to cilial transport, and is also implicated in other developmental disorders, such as  Joubert syndrome  (JS). [ 2 ]
Additionally, mutations in  HYLS1  are no longer explicitly connected to HLS in humans. [ 2 ]  Homozygous mutations removing the stop  codon  in exon 4 of  HYLS1  result in a different genomic sequence disruption to the missense mutation of HLS, and phenotypically present as JS. [ 3 ]  The ‘molar tooth sign’ of the brain, an anomaly in which cerebellar volume is reduced but cerebellar shape is retained, resembles the molar tooth and is used to identify JS. [ 2 ]  JS presents with mutations in more than 30 genes, whilst the  HYLS1  mutation is the sole cause of HLS, but is also present in the HLS2 variant form with the mutated  KIF7  gene. [ 4 ]


HLS can be readily diagnosed during pregnancy through the use of  ultrasound , which will often reveal  hydrocephaly  and an abnormal structure of the brain. [ 12 ]
Precise examination via ultrasound or at birth is necessary to rule out Meckel syndrome,  Trisomy 13 , or  Smith–Lemli–Opitz syndrome , which present with similar physiological defects. [ 7 ]  HLS can be detected at the end of the first trimester, approximately 13 weeks  gestation . [ 8 ]


No cure or treatment option for individuals with HLS currently exist. [ 12 ]  Due to the severity of the foetal defects and the poor prognosis for those with HLS, the pregnancy is often terminated. [ 7 ]  Certain prevention can only be achieved by avoiding conception if genetic testing indicates both prospective parents as carriers of the defective  HYLS1  gene. [ 9 ]


• HYLS1


Immunodeficiency 26  is a rare genetic syndrome. It is characterised by absent circulating  B  and  T cells  and normal  natural killer cells .


The features of this condition include recurrent candidiasis and lower respiratory tract infections. [ 1 ]


This condition is due to mutations in the  DNA-PKcs  gene and is inheritable in an autosomal recessive fashion. The gene is located on the long arm of  chromosome 8  (8q11.21) on the minus strand. It encodes a protein of 4128 amino acids with a predicted molecular weight of 469 kilodaltons. The encoded protein is a protein kinase that is activated by  DNA . This protein acts as a sensor for damaged DNA. [ citation needed ]


Diagnosis is made by examination of the circulating  lymphocytes  and gene sequencing. [ citation needed ]


This condition is rare. Only three cases have been described up to 2023. [ 2 ]


This condition was described in 2009 by van der Burg et al. [ 3 ]


Isodisomy  is a form of  uniparental disomy  in which both copies of a  chromosome , or parts of it, are inherited from the same parent. It differs from heterodisomy in that instead of a complete pair of homologous chromosomes, the fertilized ovum contains two identical copies of a single parental chromosome. [ 1 ] [ 2 ]  This may result in the expression of recessive traits in the offspring. [ 3 ]  Some authors use the term uniparental disomy and isodisomy interchangeably. [ 4 ]


This genetic abnormality can result in the birth of a normal child who has no obvious disability. [ 1 ]  It is associated with abnormalities in the growth of the offspring and in the placenta. [ 2 ]  Isodisomy may be a common phenomenon in human cells, and "might play a role in the pathogenesis of various nonmalignant disorders and might explain local impaired function and/or clinical variability." [ 5 ]


Isolated congenital asplenia  is a rare disease in humans that can cause life-threatening  bacterial infections  in children due to  primary immunodeficiency . [ 1 ] [ 2 ] [ 3 ] [ 4 ]  The infections can include  pneumococal   sepsis  and  meningitis . [ 2 ] [ 5 ]


ICAS is a  ribosomopathy , [ 6 ]  due to  autosomal dominant   mutation  of the  RPSA   gene   on  chromosome 3p 21. [ 4 ] [ 7 ]  Unlike  heterotaxy syndrome , [ 8 ]  the  absent spleen  (asplenia) is not associated with other structural developmental defects. [ 3 ] [ 4 ]  In some cases the  spleen  is present, but very small and nonfunctional (hyposplenism).  [ 9 ]


The spleen is an organ within the  lymphatic system  and its primary function is to filter blood. However, the spleen also plays a key role in  immune  responses as it detects pathogens within the blood and secretes  phagocytes  to fight potential infection. Without these immune functions, individuals with isolated congenital asplenia are extremely susceptible to infection.  [ 10 ]   Streptococcus pneumoniae  is a common bacteria that affects individuals with ICAS, often causes meningitis, sepsis, and  otitis media .  [ 9 ]


Juberg–Hayward syndrome  is a  rare  genetic syndrome characterised by  cleft lip and cleft palate ,  microcephaly , ptosis,  short stature ,  hypoplasia  or  aplasia  of thumbs,  dislocation  of  radial head  and fusion of  humerus  and  radius . The abnormalities in the arm lead to restriction of movement in the elbow.


These include [ 2 ]


This syndrome is caused by mutations in the establishment of cohesion 1 homolog 2 ( ESCO2 ) gene. [ 3 ]  This gene is located on the short arm of  chromosome 8  (8p21.1). Mutations in this gene also cause  Roberts/SC phocomelia syndrome . [ citation needed ]


Juberg–Hayward syndrome  is inherited in both an  autosomal recessive  and  autosomal dominant  fashion. [ citation needed ]


This condition was first described in 1969 by Juberg and Hayward. [ 4 ]


Katz syndrome  is a rare  congenital disorder , presenting as a polymalformative  syndrome  characterized by enlarged  viscera ,  hepatomegaly ,  diabetes , and skeletal anomalies that result in a short stature, cranial  hyperostosis , and typical facial features. It is probably a variant of the  autosomal   recessive  type of   Craniometaphyseal Dysplasia . [ 1 ]


Manifestations include enlarged viscera, hepatomegaly, diabetes, short stature and cranial hyperostosis. [ citation needed ]


Kaufman oculocerebrofacial syndrome,  also known as blepharophimosis-ptosis-intellectual disability syndrome, is an extremely rare  autosomal   recessive   congenital disorder  characterized by severe  mental retardation , brachycephaly, upslanting  palpebral fissures ,  eye  abnormalities, and highly arched  palate . [ 1 ] [ 3 ]  It was characterized in 1971; [ 5 ]  eight cases had been identified as of 1995. [ 6 ]  To date, the amount of cases is disputed, with sources claiming the number ranges from 14 to 31. [ 7 ] [ 8 ]


The signs and symptoms of Kaufman oculocerebrofacial syndrome are consistent with the following: [ 1 ] [ 9 ]


The cause of this condition is apparently due to mutation in the  UBE3B   gene  and is inherited via autosomal recessive manner. [ 2 ]  This gene is located at molecular location-  base pairs  109,477,410 to 109,543,628 and position 24.11 on  chromosome  12. [ 10 ]


The mechanism (or pathogenesis) of Kaufman oculocerebrofacial syndrome appears to begin due to a mutation in the E3  ubiquitin  protein ligase. ( UBE3B ).
 [ 11 ]


One finds that the normal mechanism of  UBE3B  gene is important in the  ubiquitin-proteasome system . The aforementioned system helps to remove  proteins  that have degraded. [ 12 ] [ 10 ]


However, when not working properly due to the mutation in the UBE3B gene(at least 15 mutations) results in an unstable UBE3B protein which has a negative effect on the ubiquitin-proteasome system. [ 10 ]


The diagnosis of Kaufman oculocerebrofacial syndrome can be achieved via  molecular testing  approaches. Additionally to ascertain if the individual has the condition: [ 3 ] [ 4 ]


Kaufman oculocerebrofacial syndrome differential diagnosis consists of: [ 3 ]


Treatment for this condition entails surveillance of growth and  contractures . Furthermore, the following are treatment options: [ 3 ]