Keutel syndrome  (KS) is a rare  autosomal   recessive genetic  disorder characterized by abnormal  diffuse   cartilage   calcification ,  hypoplasia  of the mid- face , peripheral  pulmonary stenosis , hearing loss, short  distal phalanges  (tips) of the fingers and mild  mental retardation . [ 2 ] [ 3 ] [ 4 ]  Individuals with KS often present with peripheral pulmonary stenosis, brachytelephalangism, sloping forehead, midface  hypoplasia , and receding  chin . It is associated with abnormalities in the gene coding for  matrix gla protein ,  MGP . [ 2 ]  Being an autosomal recessive disorder, it may be inherited from two unaffected, abnormal MGP-carrying parents. Thus, people who inherit two affected  MGP   alleles  will likely inherit KS.


It was first identified in 1972 as a novel rare genetic disorder sharing similar symptoms with  chondrodysplasia punctata . [ 2 ] [ 5 ]  Multiple forms of chondrodysplasia punctata share symptoms consistent with KS including abnormal cartilage calcification,  forceful respiration , brachytelephalangism,  hypotonia , psychomotor delay, and conductive  deafness , yet peripheral  pulmonary stenosis  remains unique to KS. [ 6 ]


No chromosomal abnormalities are reported in affected individuals, suggesting that familial  consanguinity  relates to the autosomal recessive mode of inheritance. Also, despite largely abnormal calcification of regions including the  larynx ,  tracheobronchial tree , nose,  pinna (anatomy) , and  epiglottis , patients exhibit normal serum calcium and phosphate levels. [ 7 ]


Being an extremely rare autosomal genetic disorder, differential diagnosis has only led to several cases since 1972. Initial diagnosis lends itself to facial abnormalities including sloping forehead, maxillary hypoplasia,  nasal bridge  depression, wide mouth, dental malocclusion, and receding chin. [ 4 ]   Electroencephalography  (EEG),  computed tomography  (CT) scanning, and skeletal survey are further required for confident diagnosis. Commonly, diffuse cartilage calcification and brachytelephalangism are identified by  X-radiation  (X-ray), while peripheral pulmonary arterial stenosis, hearing loss,  dysmorphic  facies, and  mental retardation  are confirmed with confidence by the aforementioned diagnostic techniques. [ 7 ]


Diagnosis is often confirmed by several abnormalities of skeletal origin. There is a sequential order of findings, according to Cormode et al., which initiate in abnormal  cartilage   calcification  and later brachytelephalangism. [ 8 ]  The uniqueness of brachytelephalangy in KS results in distinctively broadened and shortened first through fourth  distal phalanges , while the fifth distal  phalanx bone  remains unaffected. [ 9 ]  Radiography also reveals several skeletal anomalies including facial  hypoplasia  resulting in underdevelopment of the  nasal bridge  with noticeably diminished  alae nasi . In addition to distinguishable facial features, patients generally demonstrate shorter than average stature and general mild developmental delay. [ citation needed ]


Many common effects sharing similarity with  chondrodysplasia punctata  stem from cartilaginous origin. Radiography reveals extensive diffuse cartilaginous  calcification . Pulmonary  angiography  and soft tissue radiography often demonstrate significant cartilaginous  ossification  in the  trachea  and  larynx , with  perichondral  and  endochondral  centers significantly ossified in transformed cartilage. [ 10 ]  Abnormal diffuse cartilaginous ossification is typically most pronounced in the  auricles  and cartilage of the trachea and larynx, while peripheral  pulmonary stenosis  is frequently common in KS. In consanguineous parents of children with KS, one is often  phenotypically  normal, while the other is positive for pulmonary stenosis. Perhaps emanating from diffuse laryngotracheal calcification, patients often present with recurrent respiratory infection,  otitis media , and  sinusitis . [ 11 ]


Apart from diffuse abnormal cartilaginous calcification in  pulmonary  and  wikt:otic  systems, patients develop significant arterial calcification throughout the body. [ 12 ]  Such calcification is concomitant with various diseases including  diabetes ,  atherosclerosis , and  kidney  dysfunction, while patients with oral  anticoagulant  use have significant  aortic valve  and  coronary artery  calcification. [ 12 ] [ 13 ]  Although not distinctive to KS,  echocardiogram  analysis has revealed right  ventricular hypertrophy  resulting in severe pulmonary artery  hypertension  in several cases. [ 14 ]


Keutel syndrome is an autosomal recessive disorder caused by a novel  loss-of-function  mutation in the matrix Gla protein gene (MGP). MGP protein resides in the  extracellular matrix  and is implicated in inhibiting calcification though the repression of  bone morphogenetic protein 2  (BMP2). Mutations resulting in loss of consensus donor splice site at  exon  2- intron  2 junctions result in significant diffuse calcification of soft tissue cartilage. [ 14 ]  Extensive diffuse cartilaginous calcification is present in MGP-knockout mice, manifesting in vascular media replacement with a cartilaginous,  chondrocyte -like matrix, and ultimately premature death. [ 15 ]  Conversely, over expression of extracellular MGP effectively abolishes calcification in chondrocytes, suggesting that MGP may function in inhibiting passive calcification in soft tissues. [ 16 ]  Recent evidence suggests MGP is a  vitamin K  dependent protein synthesized by chondrocytes and  vascular smooth muscle  cells, where it potentiates the inhibition of cartilaginous and arterial calcification. Thus, potential vitamin K deficiency, via nutritional deficiency or  coumarin -derivative use, would render MGP uncarboxylated and inactive, thus diminishing biological function. [ 17 ] [ 18 ]  Arterial calcification resulting from MGP inactivation results in inimical prognosis, commonly seen in patients with  diabetes ,  atherosclerosis , and  renal  dysfunction. [ citation needed ]


Treatment is symptomatic, often addressing indicators associated with peripheral pulmonary artery stenosis. Laryngotracheal calcification resulting in  dyspnea  and forceful breathing can be treated with  bronchodilators  including the short and long-acting β2-agonists, and various  anticholinergics . [ citation needed ]


Prognosis is  good, yet life expectancy depends on the severity and extent of diffuse pulmonary and arterial calcification. [ citation needed ]


Keutel Syndrom was first described by the pediatric Cardiologist  Jürgen Keutel [ 5 ]  and Colleagues in 1972 in  Göttingen , Germany.


Kniest dysplasia  is a rare form of  dwarfism  caused by a mutation in the  COL2A1  gene on chromosome 12. [ 1 ]  The  COL2A1  gene is responsible for producing  type II collagen . The mutation of  COL2A1  gene leads to abnormal skeletal growth and problems with hearing and vision. What characterizes Kniest dysplasia from other type II  osteochondrodysplasia  is the level of severity and the dumb-bell shape of shortened long tubular bones. [ 2 ]


This condition was first described by Dr. Wilhelm Kniest in 1952, publishing the case history of a 3 1⁄2 year-old girl. Dr. Kniest noticed that his patient had bone deformities and restricted joint mobility. The patient also had short stature and later developed blindness, resulting from retinal detachment and glaucoma. [ 3 ]  Upon analysis of the patient's DNA in 1992, sequencing revealed deletion of a 28 base pair sequence encompassing a  splice site  in exon 12 and a G to A transition in exon 50 of the COL2A1 gene. [ 4 ]


This condition is very rare and occurs less than 1 in 1,000,000 people. Males and females have equal chances of having this condition. [ 5 ]  Currently, there is no cure for Kniest dysplasia. Alternative names for Kniest Dysplasia can include  Kniest syndrome ,  swiss cheese cartilage syndrome ,  Kniest chondrodystrophy , or  metatrophic dwarfism type II.


Because collagen plays an important role in the development of the body, people with Kniest Dysplasia will typically have their first symptoms at birth. These symptoms can include: [ 6 ]


Most symptoms are chronic and will continue to worsen as the individual ages. It is essential to have regular checkups with general doctors, orthopedist, ophthalmologists, and/or otorhinolaryngologists. This will help to detect whether there are any changes that could cause concern. [ 7 ]


Studies have shown that a mutated COL2A1 gene is responsible for all type II  chondroldysplasias , including Kniest dysplasia. It is believed that  point mutations  or the alteration of splice sites in COL2A1 domains will result in Kniest Dysplasia. The COL2A1 domain typically spans between  exon  12 and 24. Mutations that occur at a splice donor site results in the loss of function at that site. This leads to the skipping of the exon and deletion of amino acids. The loss of these amino acids result in an abnormal procollagen II structure. The structure is not stable like the normal  procollagen  II structure and is normally degraded at a faster rate. [ 8 ]


Kniest dysplasia is an  autosomal dominant  condition. [ 9 ]  This means that the person only needs to have one copy of the mutated gene in order to have the condition. People with a family history are at a higher risk of having the disease than people with no family history. A random mutation in the gene can cause a person with no family history to also have the condition. [ citation needed ]


A combination of medical tests are used to diagnosis Kniest dysplasia. These tests can include: [ 10 ]


The images taken will help to identify any bone anomalies. Two key features to look for in a patient with Kniest dysplasia is the presence of dumb-bell shaped femur bones and  coronal clefts  in the vertebrae. Other features to look for include: [ citation needed ]


Genetic Testing  - A genetic sample may be taken in order to closely look at the patient's DNA. Finding an error in the COL2A1 gene will help identify the condition as a type II chondroldysplasia. [ citation needed ]


Because Kniest dysplasia can affect various body systems, treatments can vary between non-surgical and surgical treatment. Patients will be monitored over time, and treatments will be provided based on the complications that arise. [ 11 ]


Like treatment options, the prognosis is dependent on the severity of the symptoms. Despite the various symptoms and limitations, most individuals have normal intelligence and can lead a normal life. [ citation needed ]


A recent article in 2015 reported a persistent notochord in a fetus at 23 weeks of gestation. The fetus had an abnormal spine, shortened long bones and a left clubfoot. After running postmortem tests and ultrasound, the researchers believed that the fetus suffered from  hypochondrogenesis . Hypochondrogenesis is caused when type II collagen is abnormally formed due to a mutation in the COL2A1 gene. Normally, the cartilaginous notochord develops into the bony vertebrae in a human body. The COL2A1 gene results in malformed type II collagen, which is essential in the transition from collagen to bone. This is the first time that researchers found a persistent notochord in a human body due to a COL2A1 mutation. [ 12 ]


It is named for Wilhelm Kniest. [ 13 ]


The Kvikk case  is about a variety of  birth defects  in the children of the men who served on  HNoMS  Kvikk , a  Royal Norwegian Navy   fast patrol boat  (FPB) of the  Snøgg  class .An investigation found that the ship's electronic systems were not to blame; no other cause has been established.Suspicion arose when two former  officers  accidentally met in the  orthopedic  department at  Haukeland University Hospital  in  Bergen , and it was later revealed that in all eleven children already had been born with birth defects from 1987 to 1994. [ 1 ]  In the end, the case counted 17 injured children, and it was also discovered that the phenomenon of birth defects already had started in 1983.


Among the claimed birth defects are  clubfoot ,  thumb hypoplasia ,  hip dysplasia ,  congenital heart defects , [ 2 ]  structural  brain damage ,  cataracts , and other defects. [ 3 ]  Some of the children have also had  developmental delays  and  behavioral problems . [ 4 ]


Kvikk was the only vessel in the Norwegian navy that was used as an  electronic warfare  (EW) vessel, and one widely discussed theory was that the powerful  electromagnetic radiation  from the boat's radio communication masts and  radar  led to several of those who served aboard the ship having children with clubfoot, and in some cases  stillborn  children. [ 5 ]  The idea was that the powerful radiation possibly damaged genetic material in the  sperm  of the men who worked aboard. [ 6 ]  A total of 17 out of 85 children of officers who served at Kvikk have been born with birth defects. [ 7 ]


Of the other theories about the cause of the deformities is one that  Kvikk  was the only vessel that was used to experiment with different types of camouflage paint.


In 1987 Kvikk was equipped for electronic warfare, partly by getting an extra radar sender  stern  rated to 750 watts, [ 8 ]  which then was used very actively to create  radar jamming  during exercises and tests. Kvikk went out of service as an EW-vessel in December 1994.


The  Norwegian Armed Forces  knew before the case came up that very powerful radiation had been measured on Kvikk. There had also been measured heavy radiation at other defense vessels as well as land installations that all exceeded  NATO 's limits for radiation hazard, [ 8 ] [ 9 ]  such as the  HNoMS Narvik  and  HNoMS Tjeld . Kvikk, however, is a much smaller vessel than those, and the radiation distance to the crew was thus smaller. It was also not uncommon for the crew on Kvikk to reside around the mast during noise transmissions, and they were thus directly exposed to strong electromagnetic radiation from the mast that it has been speculated in whether may have affected their genetic material. [ citation needed ]


As an additional risk factor the radar on Kvikk had a stabilizer that were made to ensure that the radar beam was kept level with the horizon so that it also would work in choppy seas, but this mechanism had a weakness that made the radar tip over many times and thus sending radiation directly down on the deck. Therefore the crew in many cases have been directly exposed to radiation at a very close hold when they were on the deck. [ 10 ]


In addition, four fathers who worked as  electronic service technicians  at the workshop of  Haakonsvern  got children with  chromosome abnormalities . They worked, among other things, to correct errors and deficiencies in telecommunications equipment on Kvikk and other marine vessels, and were therefore under testing exposed to high levels of electromagnetic radiation, mostly from radars [ 11 ]  and communications equipment.


It is shown in research from the 60's and 70's that non-ionizing radiation in the microwave range can provide genotoxic mechanisms in germ cells in animals which are then relayed to the offspring, as well as practical examples have shown that radiation have led to infertility in humans, [ 12 ]  but little recent research supports this. [ citation needed ]


The Norwegian Navy, the  Norwegian Radiation Protection Authority  (NRPA) and a research group at  Norwegian University of Science and Technology  have concluded that there is no demonstrable link between the non-ionizing radiation on board and that the children were born with birth defects. [ 10 ]  The parents in the case have stated that they don't trust the research. [ 13 ]


The case became known as the Haakonsvern Navy Base in 1996 issued a press release stating that an unusually high number of children of the employees at the naval base were damaged at birth.  Verdens Gang  (VG) was the first newspaper that took hold of the case, and the newspaper also found the relationship between the children who were born with birth defects and that their fathers had worked at Kvikk. VG immediately published a headline that read "Crown Prince  Haakon Magnus of Norway  is one of the many who is currently aboard the MTB vessels and may be exposed to radiation." [ citation needed ]


The navy quickly made a decision to investigate whether there was a correlation between the electromagnetic radiation aboard Kvikk and the genes of those who had served there, but then Kvikk was already broken up - only nine days after the original press release from Haakonsvern. [ 14 ]


After three officers in February 1996 had notified the navy  inspectorate  that they had got children with birth defects after serving on Kvikk, the navy the same year gave an internal message that they did not want to hear any more about such abnormalities from the naval staff. [ 15 ]


The navy began to investigate whether the damages in this and similar cases could be due to radar and radio radiation. In 1998 they concluded that this was not the case and that there was no relationship between serving on the ship and having children with birth defects, [ 16 ]  so that there was no basis for  liability . In the report, the Navy went far in rejecting any possible link whatsoever between birth defects to their children and that the fathers had served on Kvikk, and suggested statistical clustering as an explanation. [ 17 ]


Langer Mesomelic Dysplasia  ( LMD ) is a rare  congenital disorder  characterised by altered bone formation, which typically causes affected individuals to experience shortening of the bones of the extremities as well as an abnormally short stature.


The disease is characterized by severe shortening of long bones, affecting the limb's middle segments more than the  proximal and distal segments . There is a severe underdevelopment or complete absence of the ulna and fibula ( hypoplasia  or  aplasia ), along with a thickened and curved radius and tibia. Additionally, these anomalies can lead to deformities of the hands and feet, and there may be hypoplasia of the  lower jaw  as well. Intellectual and motor development of affected persons are normal. Adults reach approximate height of 130 cm. [ 1 ]


The disease is caused by  homozygous  or  compound heterozygous  mutations of the  short-stature homeobox gene  (SHOX), located at the  pseudoautosomal region  PAR1 of the human  sex chromosomes , or this gene's  enhancer region . In other words, it is a genetic abnormality inherited in a  recessive  manner. Carrying only one mutant  allele  ( heterozygosity ) presents as  Léri–Weill dyschondrosteosis . Mutations of the enhancer regions may be connected to less severe presentation. [ 1 ] [ 2 ]


Diagnosis may be suspected on the basis of the clinical and radiologic findings, which are already present at birth, and can supported by molecular analysis of the SHOX gene. The disease may also be suspected through ultrasound during the  second trimester  of gestation. [ 1 ]


LMD is part of the  mesomelic  and  rhizomelic   skeletal dysplasias , which are primary bone diseases where the person's short stature is due to a lack of complete bone development of the limb's long bones. [ citation needed ]


Children with Langer mesomelic dysplasia are given  Growth hormone ; it does not affect the bone anomalies, but it can increase the final height reached by 7 to 10 cm. [ 3 ] [ 4 ]  In selected patients, orthopaedic surgery may be helpful to try to gain some functionality of severely impaired joints. [ citation needed ]


Life expectancy is normal; walking may be delayed. [ 1 ]


A  laryngeal cleft  or  laryngotracheoesophageal cleft  is a rare  congenital  abnormality in the  posterior   laryngo - tracheal  wall. [ 1 ]  It occurs in approximately 1 in 10,000 to 20,000 births. [ 2 ]  It means there is a communication between the  oesophagus  and the trachea, which allows food or fluid to pass into the airway. [ 3 ]


Twenty to 27% of individuals with a laryngeal cleft also have a  tracheoesophageal fistula  and approximately 6% of individuals with a fistula also have a cleft. [ 4 ]  Other congenital anomalies commonly associated with laryngeal cleft are  gastro-oesophageal reflux ,  tracheobronchomalacia ,  congenital heart defect ,  dextrocardia  and  situs inversus . [ 5 ]  Laryngeal cleft can also be a component of other genetic syndromes, including  Pallister–Hall syndrome  and  G syndrome  ( Opitz-Frias syndrome ). [ 4 ]


Laryngeal cleft is usually diagnosed in an infant after they develop problems with feeding, such as coughing,  cyanosis  (blue lips)  and failing to gain weight over time. [ 3 ]   Pulmonary  infections are also common. [ 4 ]  The longer the cleft, the more severe are the symptoms. Laryngeal cleft is suspected after a video swallow study (VSS) shows material flowing into the airway rather than the esophagus, and diagnosis is confirmed through  endoscopic  examination, specifically  microlaryngoscopy  and  bronchoscopy . [ 4 ] [ 5 ]  If a laryngeal cleft is not seen on flexible nasopharyngoscopy, that does not mean that there is not one there.  Laryngeal clefts are classified into four types according to Benjamin and Inglis. Type I clefts extend down to the  vocal cords ; Type II clefts extend below the vocal cords and into the  cricoid cartilage ; Type III clefts extend into the  cervical  trachea and Type IV clefts extend into the  thoracic  trachea. [ 5 ]   Subclassification of type IV clefts into Type IVA (extension to 5 mm below the innominate artery) and Type IV B (extension greater than 5 mm below the innominate artery) may help with preoperative selection of those who can be repaired via transtracheal approach (Type IV A) versus a cricotracheal separation approach (type IV B). [ 6 ] [ 7 ]


Treatment of a laryngeal cleft depends on the length and resulting severity of symptoms. A shallow cleft (Type I) may not require surgical intervention. [ 5 ]  Symptoms may be able to be managed by thickening the infant's feeds. [ 5 ]  If symptomatic, Type I clefts can be sutured closed or injected with filler as a temporary fix to determine if obliterating the cleft is beneficial and whether or not a more formal closure is required at a later date. [ 8 ]  Slightly longer clefts (Type II and short Type III) can be repaired endoscopically. Short type IV clefts extending to within 5 mm below the innominate artery can be repaired through the neck by splitting the trachea vertically in the midline and suturing the back layers of the esophagus and trachea closed. [ 6 ]   A long, tapered piece of rib graft can be placed between the esophageal and tracheal layers to make them rigid so the patient will not require a tracheotomy after the surgery and to decrease chances of fistula postoperatively. [ 6 ]   Long Type IV clefts extending further than 5 mm below the innominate artery cannot be reached with a vertical incision in the trachea, and therefore are best repaired through cricotracheal resection. [ 7 ]   This involves separating the trachea from the cricoid cartilage, leaving the patient intubated through the trachea, suturing each of the esophagus and the back wall of the trachea closed independently, and then reattaching the trachea to the cricoid cartilage. [ 7 ]   This prevents the need for pulmonary bypass or extracorporeal membrane oxygenation. [ citation needed ]


Late congenital syphilitic oculopathy  is a disease of the  eye , a manifestation of  late congenital syphilis . It can appear as:


Congenital syphilis  is categorized by the age of the child.  Early congenital syphilis  occurs in children under 2 years old, and late congenital syphilis in children at or greater than 2 years old. Manifestations of late congenital syphilis are similar to those of  secondary syphilis  and  tertiary syphilis  in adults.


Majewski's polydactyly syndrome , also known as  polydactyly with neonatal chondrodystrophy type I, short rib-polydactyly syndrome type II , and  shorts rib-polydactyly syndrome , is a lethal form of  neonatal   dwarfism  characterized by  osteochondrodysplasia  ( skeletal  abnormalities in the development of  bone  and  cartilage ) with a narrow  thorax ,  polysyndactyly , disproportionately short  tibiae , thorax dysplasia, hypoplastic  lungs  and respiratory insufficiency. Associated anomalies include protruding abdomen,  brachydactyly , peculiar faces, hypoplastic  epiglottis , cardiovascular defects, renal cysts, and also genital anomalies. Death occurs before or at birth.The disease is inherited in an  autosomal recessive  pattern. [ citation needed ]


It was characterized in 1971. [ 1 ]


A  malformative syndrome  (or  malformation syndrome )  is a recognizable pattern of  congenital anomalies  that are known or thought to be causally related (VIIth International Congress on Human Genetics).


Najjar syndrome


Malouf syndrome  (also known as "congestive cardiomyopathy- hypergonadotropic hypogonadism  syndrome") is a  congenital disorder  that causes one or more of the following symptoms:  intellectual disability ,  ovarian   dysgenesis , congestive  cardiomyopathy , broad nasal base,  blepharoptosis , and bone abnormalities, and occasionally  marfanoid habitus  (tall stature with long and thin limbs, little  subcutaneous fat ,  arachnodactyly , joint  hyperextension ,  narrow face , small chin, large testes, and  hypotonia ). [ 2 ]


This congenital disease was first classified in 1985 by Dr. Joe Malouf, who performed a case study on two sisters that displayed this rare syndrome. [ 3 ]  The study consisted of two sisters that presented with hypergonadotropic hypogonadism, dilated cardiomyopathy, blepharoptosis, and a broad nasal base. [ 4 ]  Upon further analysis of their genetic lineage, it was found that the parents of the sisters were first-degree cousins; Malouf then classified the syndrome as a familial disorder. [ 5 ]  In 1992, a new case study of an 18-year-old female conducted by Narahara et al. resulted in similar findings as Malouf. [ 6 ]  Although the prevalence of Malouf syndrome is unknown, there are less than 20 affected families discussed in literature. [ 7 ]  While there is no specific cure for Malouf syndrome, symptoms can be treated. [ 8 ]  The treatment options are individualized and should be determined by a doctor or specialist.


The main symptoms of this disease are  hypergonadotropic hypogonadism  and  cardiomyopathy , whose coexistence is extremely rare. [ 5 ]  It is characterized by a combination of features that can affect the skeletal, cardiovascular, and skin systems.


Symptoms: [ 7 ]


Note: it is possible that males with Malouf syndrome display cardiomyopathy but not testicular dysgenesis [ 24 ]


Malouf syndrome involves an autosomal recessive inheritance pattern in that it is a recessive trait that is inherited. [ 24 ]  It is caused by a heterozygous missense mutation in the LMNA gene located on chromosome 1 (1q22). [ 24 ]  The person inherits two copies of this mutation from both of the parents - meaning both parents are carriers of this mutation - leading to the development of the syndrome. The LMNA gene encodes for lamin A and lamin C which are important proteins produced by almost every type of cell in the body. [ 25 ] [ 26 ]  The lamin family of proteins are components of the nuclear lamina that consists of a protein network within the inner nuclear membrane that determine nuclear stability, chromatin structure and gene expression. [ 27 ]  Mutations in this gene can lead to several diseases besides Malouf syndrome, such as  familial partial lipodystrophy ,  limb girdle muscular dystrophy , and  Hutchinson-Gilford progeria syndrome , [ 27 ]  therefore making it harder to distinguish whether a patient is displaying signs of Malouf syndrome or some other disease. The LMNA mutation can show up in many different tissues including cardiac, skeletal, nervous, adipose, and cutaneous tissue. [ citation needed ]


The most common heterozygous mutations found in the LMNA gene are a heterozygous de novo ala57-to-pro substitution (A57P), which means the Alanine amino acid at position 57 was substituted by a Proline, resulting from a 584G-C transversion in the LMNA gene and a de novo 176T-C transition in exon 1 leading to a leu59-to-arg (L59R) substitution. [ 25 ]


Further genetic research and advanced molecular techniques are necessary to identify the specific genetic defects and pathways involved in Malouf syndrome. The genetic basis of Malouf syndrome remains incompletely understood, contributing to challenges in diagnosis and management. [ citation needed ]


There is no set criteria used to diagnose Malouf syndrome. Signs and symptoms such as congestive or dilated cardiomyopathy, ovarian dysgenesis in females or primary testicular failure in males, intellectual disability, broad nasal base, blepharoptosis, skin lesions, and skeletal abnormalities are used as a reference to diagnosis this rare disease, and  genetic testing  of the LMNA gene can serve as a way to confirm a diagnosis. [ 2 ]


Malouf syndrome was first diagnosed in 1985 by Dr. Joe Malouf. Dr. Malouf examined two sisters who exhibited congestive cardiomyopathy associated with ovarian dysgenesis, secondary hypergonadotropic hypogonadism, bilateral ptosis, and prominent nasal bones. [ 28 ]  Dr. Malouf noted that this disease is familial - and therefore congenital - as the two sisters were children of first degree cousins. [ 3 ]


In 1992, Kouji Narahara examined an 18-year-old girl who displayed the same symptoms seen by Dr. Malouf in his patients. [ 28 ]  She was described as having delayed intellectual development, mild cardiomegaly, broad nasal base and several signs of Marfan syndrome such as small stature, arachnodactyly, and a large arm span. With further testing, it was found that she had several  electrocardiography (ECG)  deviations which were concluded to be left-side dilated cardiomyopathy and congestive heart failure. In addition to cardiomyopathy, many of her reproductive organs were also significantly impacted such as hypoplasia of her uterus, vagina, and fallopian tubes. Dr. Narahara was able to conclude that the girl had Malouf syndrome because it is extremely rare to see gonadal dysgenesis and cardiomyopathy in the same patient, which both his patient and Dr. Malouf's patients exhibited. [ citation needed ]


Diagnosis of this syndrome is sometimes conflicting as the symptoms displayed match those of other diseases such as  limb girdle muscular dystrophy ,  Hutchinson-Gilford progeria syndrome , Noonan syndrome et cetera. As a result, it has been often questioned as to whether Malouf syndrome truly is a new syndrome that should be accepted. [ 29 ]


In particular, Noonan syndrome has been the most significant condition that is considered in the differential diagnosis of Malouf syndrome because of the similarity in its signs and clinical manifestations to those of Malouf syndrome. However, certain fundamental signs and symptoms that are unique only to Malouf syndrome were able to be the distinguishing factor in diagnosis. Some of these signs and symptoms include small stature, abnormalities of the thorax, and a webbed neck. [ citation needed ]


Despite all of this, providers are strongly encouraged to keep Malouf syndrome in mind with the differential diagnosis of dilated cardiomyopathy until further evidence is discovered which will lead to a more guided approach to diagnosing patients. [ citation needed ]


Due to the clinically overlapping characteristics, distinguishing Malouf syndrome from other diseases can be challenging. For instance, Malouf syndrome shares similarities with Marfan syndrome, such as a tall and slender build, long limbs, and mitral valve prolapse, making it difficult to differentiate between the two based solely on physical examination. Additionally, other connective tissue disorders like Ehlers-Danlos syndrome, Loeys-Dietz syndrome, and homocystinuria can present with overlapping features such as hypermobility, skin laxity, and cardiovascular anomalies. Therefore, a thorough clinical evaluation, including detailed medical history and, where possible, genetic testing, is crucial for an accurate diagnosis and appropriate management. [ citation needed ]


Due to the rare nature of the disease, it has been difficult to understand any underlying mechanisms that cause Malouf syndrome. At its current state, there are no specific treatment regimens or therapies to specifically address Malouf syndrome. However, there are ways to manage the symptoms associated with the disease and other lamin-associated dilated cardiomyopathies. [ 34 ] [ 35 ]  Specifically, with respect to Lamin A/C (LMNA) cardiomyopathy, the current treatment follows the standard heart failure regimen. [ 36 ]  As noted by Dr. Zhang et al., the treatment for standard heart failures in relation to LMNA cardiomyopathy uses "beta-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and aldosterone antagonists, but the specific efficacy in this population is undetermined." [ 36 ]  Depending on the patient's case, treatment may need a variety of medications to address the symptoms. [ 37 ]


Drugs : [ 37 ]  used to treat dilated cardiomyopathy.


Angiotensin-converting enzyme (ACE) inhibitors-  This type of medicine enlarges blood vessels and lowers blood pressure in order to improve an individual's blood flow. Some of the side effects are dry cough, low blood pressure, low white blood cell count, and kidney or liver problems. [ 38 ]  Examples: Lisinopril (Zestril), Benazepril (Lotensin).


Angiotensin II receptor blockers (ARBs)-  ARBs are an alternative blood pressure-lowering medication that can be used if a person cannot tolerate ACE inhibitors. Some of the side effects are hyperkalemia, hypotension, and acute renal failure. [ 39 ]  Examples: Losartan (Cozaar), Olmesartan (Benicar).


Anticoagulants - This type of drug helps in preventing blood clots but can cause bruising or bleeding. [ 40 ]  Examples: Rivaroxaban (Xarelto), Apixaban (Eliquis), Warfarin (Coumadin).


Sacubitril/Valsartan (Entresto)-  This combination drug includes an ARB and ACE inhibitor to help pump blood from your heart to the rest of your body. This drug is mainly for people with chronic heart failure. Common side effects include cough, hyperkalemia, and  angioedema . [ 41 ]


Beta-blockers-  This class of drug slows your heart rate and lowers blood pressure. This medication may also prevent the harmful effects of stress hormones. Some of the side effects of this medication include dizziness, low blood pressure, fatigue, and reduced exercise tolerance. [ 42 ]  Examples: Metoprolol (Betaloc or Lopressor), Atenolol (Tenormin).


Diuretics-  This type of drug removes excess fluid and salt from the body as well as the lungs, as excess fluid in the body can strain the heart by forcing it to pump harder. Some of the side effects include increased urination and hyperkalemia. [ 43 ]  Examples: Furosemide (Lasix), Hydrochlorothiazide (Microzide).


Digoxin (Lanoxin)-  The purpose of this drug is to strengthen heart muscle contractions and slow down the heartbeat. This drug can reduce heart failure symptoms and improve your ability to be more active. One thing to note is that the use of digoxin requires frequent monitoring due to its narrow therapeutic window. Some of the side effects include rash, headache, hypokalemia, and arrhythmias. [ 44 ]


Ivabradine (Corlanor)-  This drug restores normal heartbeat by slowing down and regulating the heart rate. It is indicated for the treatment of stable angina pectoris and heart failure with reduced ejection fraction but has seen an increasing role in treating dilated cardiomyopathy due to its improvement of cardiac function. Some side effects of Ivabradine include bradycardia (slow heart rate), atrial fibrillation, and hypertension. [ 45 ]


Therapeutic devices: [ 37 ]  can be surgically implemented to help treat dilated cardiomyopathy.


Biventricular pacemaker-  This device sends out electrical signals in order to control contractions between the left and right ventricles. It is used for people who have heart failure and irregular heartbeats.


Implantable cardioverter-defibrillators (ICD)-  Although this device does not treat cardiomyopathy itself, it does help prevent arrhythmias, which are commonly caused by cardiomyopathy. Implantable cardioverter-defibrillators monitor the heartbeat and send electrical shocks to control any rapid or abnormal rhythms. This device can also serve as a pacemaker which works similarly to keep the heart beating at a normal rate and rhythm).


Left ventricular assist devices (LVAD)-  This device is attached to the heart and either the abdomen or chest in order to help the weakened heart pump blood. It is usually considered after other approaches have proven unsuccessful and can be used as treatment while waiting for a heart transplant.


Hypergonadotropic hypogonadism hormone replacement therapy: [ citation needed ]


Hormonal replacement therapy (testosterone, estrogen, progesterone, pituitary hormones, et cetera)-  This treatment consists of taking medications containing the hormone that the body is lacking to replace the ones that the body no longer produces. These medications can come in the form of pills, patches, gels, or injections. [ 46 ] [ 47 ]


It is important to note , Malouf syndrome  will require  regular monitoring.  Due to the nature of the disease, and given the potential for progressive symptoms, ongoing monitoring and evaluation by specialists in cardiology, dermatology, and orthopedics are recommended. Genetic counseling may also be beneficial for affected individuals and their families to understand the inheritance pattern and implications.


In summary, Malouf syndrome is a complex disorder requiring a tailored approach to care. As research advances, further understanding of the genetic underpinnings of this condition may lead to more precise diagnostic tools and targeted therapies.


The prevalence of Malouf syndrome is unknown at the moment and has not been fully defined. About 20 families from around the world, whose members have cardiogential syndrome, have been found in literature. However, the prevalence of familial dilated cardiomyopathy ranges from 30 to 50% cases, with 40% having an identifiable genetic cause. [ 48 ]  Dilated cardiomyopathy was originally classified as a rare disease, but the possibility of a familiar substrate was ignored. Dilated cardiomyopathy was later found to be a major cause of heart failure, especially among young patients. [ 48 ]  Dilated cardiomyopathy began to be identified as a systemic condition rather than an isolated disease. [ 48 ]  Even despite these major efforts and contributions, the incidence and prevalence of dilated cardiomyopathy remain unknown. [ 48 ]


Malpuech facial clefting syndrome , also called  Malpuech syndrome  or  Gypsy type facial clefting syndrome , [ 1 ]  is a rare  congenital   syndrome . It is characterized by  facial clefting  (any type of cleft in the bones and  tissues  of the face, including a  cleft lip and palate ), a  caudal   appendage  (a "human tail"), [ 2 ] [ 3 ]   growth deficiency ,  intellectual  and  developmental disability , and abnormalities of the renal system (kidneys) and the male genitalia. [ 4 ]  Abnormalities of the heart, and other skeletal malformations may also be present. [ 5 ]  The syndrome was initially described by Georges Malpuech and associates in 1983. [ 6 ]  It is thought to be genetically related to  Juberg-Hayward syndrome . Malpuech syndrome has also been considered as part of a spectrum of congenital genetic disorders associated with similar facial, urogenital and skeletal anomalies. Termed "3MC syndrome", this proposed spectrum includes Malpuech,  Michels  and  Mingarelli-Carnevale  (OSA) syndromes. [ 7 ] [ 8 ]   Mutations  in the  COLLEC11  and  MASP1  genes are believed to be a cause of these syndromes. [ 9 ]  The  incidence  of Malpuech syndrome is unknown. The pattern of inheritance is  autosomal   recessive , which means a defective (mutated) gene associated with the syndrome is located on an autosome, and the syndrome occurs when two copies of this defective gene are inherited. [ 10 ]


Malpuech syndrome is congenital, being apparent at birth. It is characterized by a feature known as facial clefting. Observed and noted in the initial description of the syndrome as a cleft lip and palate, [ 6 ]  facial clefting is identified by clefts in the bones, muscles and tissues of the  face , including the lips and  palate . The forms of cleft lip and palate typically seen with Malpuech syndrome are midline (down the middle of the lip and palate) [ 11 ]  or bilateral (affecting both sides of the mouth and palate). [ 10 ]  Facial clefting generally encompasses a wide range of severity, ranging from minor anomalies such as a  bifid  (split)  uvula , to a cleft lip and palate, to major developmental and structural defects of the facial bones and soft tissues. [ 12 ]  Clefting of the lip and palate occurs during  embryogenesis . [ 13 ] [ 14 ]  Additional facial and  ortho-dental  anomalies that have been described with the syndrome include:  hypertelorism  (unusually wide-set eyes, sometimes reported as  telecanthus ), narrow  palpebral fissures  (the separation between the upper and lower eyelids) and  ptosis  (drooping) of the eyelids, frontal bossing (prominent eyebrow ridge) with  synophris , highly arched eyebrows, wide  nasal root  and a flattened nasal tip,  malar   hypoplasia  (underdeveloped  upper cheek bone ),  micrognathia  (an undersized  lower jaw ), and prominent  incisors . Auditory anomalies include an enlarged  ear ridge , and  hearing impairment  associated with congenital  otitis media  (or "glue ear",  inflammation  of the  middle ear ) and  sensorineural hearing loss . [ 4 ] [ 15 ] [ 16 ]


Another feature identified with Malpuech syndrome is a  caudal  appendage. [ 1 ] [ 3 ]  A caudal appendage is a congenital outgrowth stemming from the  coccyx  (tailbone). Present in many non-human animal species as a typical  tail , this feature when seen in an infant has been described as a "human tail". [ 2 ] [ 17 ]  This was observed by Guion-Almeida (1995) in three individuals from Brazil. The appendage on  X-rays  variously appeared as a prominent protrusion of the coccyx. [ 3 ]  On a physical examination, the appendage resembles a nodule-like stub of an animal tail. [ 18 ]


Deficiencies such as  intellectual disability ,  learning disability ,  growth retardation  and  developmental delay  are common. Psychiatric manifestations that have been reported with the syndrome include  psychotic behavior ,  obsessive–compulsive disorder , loss of inhibition,  hyperactivity ,  aggression , fear of physical contact, and compulsive actions like  echolalia  (repeating the words spoken by another person). Neuromuscular  tics  have also been noted. [ 4 ] [ 15 ]


Urogenital abnormalities, or those affecting the  urinary  and  reproductive systems , are common with the syndrome. Malpuech et al. (1983) and Kerstjens-Frederikse et al. (2005) reported variously in affected males a  micropenis ,  hypospadias  (a congenital mislocation of the  urinary meatus ),  cryptorchidism  ( ectopic  or undescended  testes ), bifid (split) and underdeveloped  scrotum , and an obstructive  urethral valve . [ 4 ] [ 6 ]  An affected boy was also reported by Reardon et al. (2001) with left  renal agenesis , an enlarged and downwardly displaced right  kidney , cryptorchidism and a  shawl scrotum . [ 7 ]  Other malformations that have been noted with the syndrome are  omphalocele [ 3 ]  and an  umbilical hernia . [ 19 ]


Congenital abnormalities of the  heart  have also been observed with Malpuech syndrome. From a healthy Japanese couple, Chinen and Naritomi (1995) described the sixth child who had features consistent with the disorder. This two-month-old male infant was also affected by cardiac anomalies including  patent ductus arteriosus  (PDA) [ 20 ]  and  ventricular septal defect . [ 5 ]  The opening in the  ductus arteriosus  associated with PDA had been  surgically repaired  in the infant at 38 days of age. A number of minor skeletal aberrations were also reported in the infant, including  wormian bones  at the  lambdoid sutures . [ 5 ]


Malpuech syndrome, as with the other disorders within the 3MC syndrome consideration, is caused by mutations in the  COLLEC11  and  MASP1  genes. In an investigation by Rooryck et al. (2011), eleven families affected by 3MC syndrome were studied, which resulted in the identification of these two mutations. Both genes encode proteins of the  lectin complement pathway , which plays a role in the  complement system  of  innate , or non-specific immunity in humans and other species. [ 9 ]


The  COLLEC11 , or  CL-K1  gene is located on the short arm of  chromosome   2  (2p25.3) in humans. [ 21 ]  The CL-K1 protein is a  C-type lectin , and belongs to the  collectin  family of these proteins. Other than its role in innate immunity, the protein is thought to be involved in the development of tissues including craniofacial cartilage, the heart and kidney during embryogenesis. This function in facial development was corroborated through study of the  zebrafish , where mutations in its version of  CL-K1  contributed to craniofacial abnormalities (such as  Craniofacial clefts ) possibly associated with errors in  neural crest  cell migration. [ 9 ]


The  MASP1 , or  Mannan-binding Serine Protease I  gene is located on the long arm of human  chromosome 3  at 3q27-q28. [ 22 ]  The protein is a type of connectin called a  mannan-binding lectin , which plays a role in innate immunity by binding to  pathogens  such as  viruses  including  HIV . [ 23 ]


As described by Sirmaci et al. (2010), three Turkish individuals from two  consanguineous  families (the children of relatives such as cousins are said to be in a consanguineous family) with various characteristics of 3MC syndrome, including facial dysmorphism and a caudal appendage, were evaluated. Investigation of  homologous chromosomes  through  gene mapping  revealed an  autozygous region  (a  location  on a chromosome where both alleles of a gene originate from a common ancestor) at chromosome 3q27 in both families. In one family, a  missense mutation  in  MASP1  at this location resulted in the replacement of the  amino acid   glycine  by  arginine  at position 687 in the  gene sequence . The mutation  cosegregated  with the observed phenotype. In individuals from the second family,  DNA sequencing  of  MASP1  showed a  nonsense mutation  that resulted in a deactivation of  tryptophan  at position 290 in the gene, that also cosegregated with the phenotype. Both mutations occur in a  form  of  MASP1  known to process  IGFBP5 ; loss of this function associated with mutation of  MASP1  causes disruptions in the availability of  insulin-like growth factor  during craniofacial and musculoskeletal development during the embryonic period. These results indicate that mutations in  MASP1  are responsible for an array of features found with malformation disorders including Malpuech syndrome. [ 24 ]


The syndrome is inherited in an autosomal recessive manner. [ 10 ]  This means the defective gene(s) responsible for the disorder ( COLLEC11 ,  MASP1 ) is located on an autosome (chromosomes 2 and 3 are autosomes), and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both  carry  one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder. [ citation needed ]


It is suggested that the  diagnostic criteria  for Malpuech syndrome should include cleft lip and/or palate, typical associated facial features, and at least two of the following: urogenital anomalies, caudal appendage, and growth or developmental delay. [ 25 ]
Due to the relatively high rate of hearing impairment found with the disorder, it too may be considered in the diagnosis. Another congenital disorder,  Wolf-Hirschhorn  (Pitt-Rogers-Danks) syndrome, shares Malpuech features in its diagnostic criteria. Because of this lacking differentiation,  karyotyping  (microscopic analysis of the chromosomes of an individual) can be employed to distinguish the two. Whereas deletions in the short arm of  chromosome 4  would be revealed with Wolf-Hirschhorn, a karyotype without this aberration present would favor a Malpuech syndrome diagnosis. Also, the karyotype of an individual with Malpuech syndrome alone will be normal. [ 15 ]


Malpuech syndrome has been shown to have physical, or  phenotypical  similarities with several other genetic disorders. A report by Reardon et al. (2001) of a nine-year-old boy exhibiting facial, caudal and urogenital anomalies consistent with Malpuech syndrome, who also had skeletal malformites indicative of Juberg-Hayward syndrome, suggests that the two disorders may be  allelic  (caused by different  mutations  of the same  gene ). [ 7 ]


Along with several other disorders that have similar, or overlapping features and autosomal recessive inheritance, Malpuech syndrome has been considered to belong under the designation "3MC syndrome". Titomanlio et al. (2005) described a three-year-old female known to have  Michels syndrome . In their review of the physical similarities between Michels, Malpuech and Mingarelli-Carnevale syndromes—particularly the facial appearance including instances of cleft lip and palate, and ptosis, and a similarity of congenital abdominal and urogenital anomalies—they believed the syndromes may represent a spectrum of genetic disorders rather than three individual disorders. They initially suggested this spectrum could be named 3MC (Michels-Malpuech-Mingarelli-Carnevale) syndrome. [ 8 ]  This conclusion and the name 3MC syndrome was supported by Leal et al. (2008), who reported a brother and sister with an array of symptoms that overlapped the various syndromes. [ 26 ]  Further assertion of 3MC syndrome was by Rooryck et al. (2011) in an elaboration of its cause. [ 9 ]


Many of the congenital malformations found with Malpuech syndrome can be corrected surgically. These include cleft lip and palate, omphalocele, urogenital and craniofacial abnormalities, skeletal deformities such as a caudal appendage or scoliosis, and hernias of the umbilicus. The primary area of concern for these procedures applied to a neonate with congenital disorders including Malpuech syndrome regards the logistics of anesthesia. Methods like  tracheal intubation  for management of the airway during  general anesthesia  can be hampered by the even smaller, or maldeveloped mouth of the infant. For  regional anesthesia , methods like  spinal blocking  are more difficult where scoliosis is present. In a 2010 report by Kiernan et al., a four-year-old girl with Malpuech syndrome was being prepared for an unrelated  tonsillectomy  and  adenoidectomy . While undergoing intubation, insertion of a  laryngoscope , needed to identify the airway for the placement of the  endotracheal tube , was made troublesome by the presence of  micrognathia  attributed to the syndrome. After replacement with a laryngoscope of adjusted size, intubation proceeded normally. Successful general anesthesia followed. [ 16 ]


A rare follow-up of a male with Malpuech syndrome was presented by Priolo et al. (2007). Born at term from an uneventful pregnancy and delivery, the infant underwent a surgical repair of a cleft lip and palate. No problems were reported with the procedure. A heart abnormality,  atrial septal defect , was also apparent but required no intervention. At age three years, intellectual disability,  hyperactivity  and  obsessive compulsive disorder  were diagnosed; hearing impairment was diagnosed at age six, managed with the use of  hearing aids . Over the course of the decade that followed, a number of  psychiatric  evaluations were performed. At age 14, he exhibited a fear of physical contact; at age 15, he experienced a severe  psychotic  episode, characterized by agitation and a loss of sociosexual inhibition. This array of symptoms were treated  pharmacologically  (with prescription medications). He maintained a low level of mental deficiency by age 17, with moments of compulsive  echolalia . [ 15 ]


The  incidence  of Malpuech syndrome has not been determined. [ 16 ]  A 1999 report by Crisponi et al. suggested that only about 12 individuals worldwide were affected by the disorder at that time. [ 19 ]  The syndrome was first reported by Guilliaume Malpuech and colleagues in 1983, observed in four children of unspecified gender in what was described as a  gypsy  family. The children included three siblings and their first cousin; the family was known to be highly  consanguineous . [ 6 ] [ 15 ]


Marden–Walker syndrome  ( MWS ) is a rare  autosomal   recessive   congenital disorder . [ 1 ] [ 2 ]  It is characterized by  blepharophimosis ,  microcephaly ,  micrognathia , multiple  joint   contractures ,  arachnodactyly ,  camptodactyly ,  kyphoscoliosis  and delayed  motor development  and is often associated with  cystic   dysplastic   kidneys ,  dextrocardia ,  Dandy–Walker malformation  and  agenesis of corpus callosum . [ 3 ]


Most of the signs of MWS are present during the neonatal period. The most common signs at this state are multiple congenital joint contractures, dysmorphic features with mask-like face,  blepharophimosis ,  ptosis ,  micrognathia , cleft or high arched palate, low-set ears,  arachnodactyly , chest deformation as pectus,  kyphoscoliosis  and absent deep tendon reflexes are frequent minor malformations have also been described and consist of renal anomalies, cardiovascular abnormalities,  hypospadias ,  omphalomesenteric  duct, hypertrophic pyloric stenosis and duodenal bands, hypoplastic right lower lobe of the lung, displacement of the  larynx  to the right and vertebral abnormalities, cerebral malformations. [ 4 ]


The natural history of MWS is not well known: many patients died in infancy and clinical follow-up has been reported in few surviving adults. However, diagnosis may be more difficult to establish in adults patients, such as:  blepharophimosis ,  contractures ,  growth retardation , and  developmental delay , whereas minor face anomalies are less noticeable as the patient grows older. [ 5 ]


MWS is a  heterogeneous , initially described as a syndrome. But this condition is more on the lines of a  phenotypic  expression of various heterogeneous diseases and belongs to the second group in the classification of  arthrogryposis . Unknown congenital  myopathy  has been suspected to underlie MWS due to muscular involvement, but extension of the  neuromuscular  systems failed to identify a primary myopathy in patients with MWS. Secondary muscle involvement from a CNS lesion may occur. This could lead to congenital weakness with hypoatonia deep tendon reflex. [ 6 ]


MWS is inherited in an autosomal recessive manner. [ 2 ]  This means the defective gene responsible for the disorder is located on an  autosome , and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both  carry  one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder. [ citation needed ]


Though the pathomechanism of Marden–Walker syndrome is unknown, it may be caused by a genetic defect which manifests as a  dysfunctional molecular mechanism  in the primary  cilia  structures of the  cell .  These  organelles  are present in many cellular types throughout the  human  body.  The cilia defects adversely affect "numerous critical developmental signaling pathways" essential to cellular development. [ 3 ]


The only treatment for MWS is only symptomatic, with multidisciplinary management [ 7 ]


There have been 30 cases of Marden-Walker Syndrome reported since 1966. The first case of this was in 1966 a female infant was diagnosed with  blepharophimosis ,  joint contractures , arachnodactyly and growth development delay. She ended up dying at 3 months due to pneumonia. [ citation needed ]


Marfanoid  (or  Marfanoid habitus ) is a constellation of signs resembling those of  Marfan syndrome , including long limbs, with an arm span that is at least 1.03 of the height of the individual, and a crowded oral maxilla, sometimes with a high arch in the palate,  arachnodactyly , and  hyperlaxity .


Arachnodactyly  (long fingers),  long limbs ,  scoliosis  (curved spine), a hidden feature of bony lip growth towards vestibular aqueduct (which can be seen in CT scan reports), and imprecise articulation of speech due to  high-arched palate  are all considered Marfanoid symptoms. Language and cognition can be affected in neonatal Marfan syndrome where intellectual disability exists. Hearing may be impaired, either by conductive loss due to hypermobility of  ossicles , by inflamed  tympanic membrane , or sensorineurally through the  vestibular aqueduct . In cases with hearing impairment, giddiness and imbalance may co-occur. Other symptoms include crowding of teeth and long or flat feet, often with hammer toes. [ citation needed ]


Marfanoid habitus is a constellation of symptoms which are generally associated with other syndromes such as Ehlers-Danlos syndrome, Perrault syndrome and Stickler syndrome. Associated conditions include:


Medical diagnostic criteria to differentiate Marfanoid habitus  from  Marfan syndrome : [ citation needed ]


Marinesco–Sjögren syndrome  ( MSS ), sometimes spelled  Marinescu–Sjögren syndrome , is a rare  autosomal   recessive  disorder.


The syndrome causes cerebellar  ataxia  (balance and coordination problems), intellectual disability, congenital  cataracts  in early childhood, muscle weakness, inability to chew food, thin brittle fingernails, and sparse hair. [ 1 ] : 578


Small stature, mild to severe intellectual disability and  dysarthria  (slow, imprecise speech) are usually present. Various skeletal abnormalities (e.g., curvature of the spine) and hypergonadotropic  hypogonadism  often occur. Muscle weakness is progressive, but life expectancy is near normal. [ citation needed ]


Marinesco–Sjögren syndrome can be associated with  mutations  of the  SIL1   gene . [ 2 ] [ 3 ]


SIL1  gene is located on  chromosome   5q31.2 [ 4 ]


Diagnosis of MSS is based on clinical symptoms,  magnetic resonance imaging  (MRI) of the brain ( cerebellar  atrophy particularly involving the  cerebellar vermis ), and  muscle biopsy . [ citation needed ]


DDx includes Congenital Cataracts Facial Dysmorphism Neuropathy (CCFDN), Marinesco–Sjögren like syndrome with chylomicronemia, carbohydrate deficient  glycoprotein  syndromes,  Lowe syndrome , and  mitochondrial disease . [ citation needed ]


Marinesco–Sjögren-like syndrome is a very rare  genetic disorder  which is characterized by symptoms similar to those shown by people with Marinesco–Sjögren syndrome, the symptoms (of this variant of MSS) being infantile  hypotonia ,  ataxia ,  cataracts ,  intellectual disabilities ,  cerebellar atrophy , myopathic alterations, vascular degeneration, and adipose tissue proliferation. [ 5 ]


Treatment for MSS is symptomatic and supportive including physical and occupational therapy, speech therapy, and special education.  Cataracts  must be removed when vision is impaired, generally in the first decade of life. Hormone replacement therapy is needed if  hypogonadism  is present. [ citation needed ]


Members of the  MOWA Band of Choctaw Indians , a state-recognized tribe located in southwest  Alabama , have a high frequency of Marinesco–Sjögren syndrome and have been the subject of study. [ 6 ] [ 7 ]  They are the only known population in the United States to suffer from the rare disease. [ 8 ]


It is named for  Gheorghe Marinescu  and  Torsten Sjögren . [ 9 ]


Maturity-onset diabetes of the young  ( MODY ) refers to any of several  hereditary  forms of  diabetes mellitus  caused by mutations in an  autosomal dominant gene  disrupting  insulin  production. [ 1 ]  Along with  neonatal diabetes , MODY is a form of the conditions known as monogenic diabetes. While the more common types of diabetes (especially  type 1  and  type 2 ) involve more complex combinations of causes involving multiple genes and environmental factors, each forms of MODY are caused by changes to a single gene (monogenic). [ 2 ]   HNF1A-MODY ( MODY 3 ) are the most common forms.


Robert Tattersall and Stefan Fajans initially identified the phenomenon known as maturity onset diabetes of the young in a classic study published in the journal  Diabetes  in 1975. [ 3 ]


MODY is the final diagnosis in 1%–2% of people initially diagnosed with diabetes. The prevalence is 70–110 per million people. 50% of first-degree relatives will inherit the same mutation, giving them a greater than 95% lifetime risk of developing MODY themselves. For this reason, correct diagnosis of this condition is important. Typically patients present with a strong family history of diabetes (any type) and the onset of symptoms is in the second to fifth decade. [ citation needed ]


There are two general types of clinical presentation. [ citation needed ]


MODY cases may make up as many as 5% of presumed type 1 and type 2 diabetes cases in a large clinic population. While the goals of diabetes management are the same no matter what type, there are two primary advantages of confirming a diagnosis of MODY. [ citation needed ]


As it occurs infrequently, many cases of MODY are initially assumed to be more common forms of diabetes: type 1 if the patient is young and not overweight, type 2 if the patient is overweight, or  gestational diabetes  if the patient is pregnant. Standard diabetes treatments (insulin for type 1 and gestational diabetes, and  oral hypoglycemic agents  for type 2) are often initiated before the doctor suspects a more unusual form of diabetes. [ citation needed ]


The recognised forms of MODY are all due to ineffective insulin production or release by  pancreatic   beta cells . Several of the defects are  mutations  of  transcription factor   genes . One form is due to mutations of the  glucokinase  gene. For each form of MODY, multiple specific mutations involving different  amino acid  substitutions have been discovered. In some cases, there are significant differences in the activity of the mutant gene product that contribute to variations in the clinical features of the diabetes (such as degree of insulin deficiency or age of onset). [ citation needed ]


The following characteristics suggest the possibility of a diagnosis of MODY in hyperglycemic and diabetic patients: [ 4 ]


The diagnosis of MODY is confirmed by specific  gene  testing available through commercial laboratories.


MODY is inherited in an  autosomal dominant  fashion, and most patients therefore have other members of the family with diabetes;  penetrance  differs between the types (from 40% to 90%).


A newly discovered monogenetic form of diabetes is marked by a missense variant in the RyR2 gene. [ 18 ]  It has not yet received a MODY type.


By definition, the forms of MODY are autosomal dominant, requiring only one abnormal gene to produce the disease; the severity of the disease is moderated by the presence of a second, normal allele which presumably functions normally. However, conditions involving people carrying two abnormal alleles have been identified. [ 19 ]  Unsurprisingly, combined (homozygous) defects of these genes are much rarer and much more severe in their effects. [ citation needed ]


Homozygous mutations in the other forms have not yet been described. Those mutations for which a homozygous form has not been described may be extremely rare, may result in clinical problems not yet recognized as connected to the monogenic disorder, or may be lethal for a fetus and not result in a viable child. [ citation needed ]


In some forms of MODY, standard treatment is appropriate, though exceptions occur:


Chronic hyperglycemia due to any cause can eventually cause blood vessel damage and the  microvascular complications of diabetes . The principal treatment goals for people with MODY — keeping the blood sugars as close to normal as possible ("good  glycemic control "), while minimizing other vascular risk factors — are the same for all known forms of diabetes. [ citation needed ]


The tools for management are similar for all forms of diabetes: blood testing, changes in  diet , physical  exercise ,  oral hypoglycemic agents , and insulin injections. In many cases these goals can be achieved more easily with MODY than with ordinary types 1 and 2 diabetes. Some people with MODY may require insulin injections to achieve the same  glycemic control  that another person may attain with careful eating or an oral medication. [ citation needed ]


When oral hypoglycemic agents are used in MODY, the sulfonylureas remain the oral medication of first resort. When compared to patients with type 2 diabetes, MODY patients are often more sensitive to sulphonylureas, such that a lower dose should be used to initiate treatment to avoid hypoglycaemia. Patients with MODY less often suffer from obesity and  insulin resistance  than those with ordinary type 2 diabetes (for whom insulin sensitizers like  metformin  or the  thiazolidinediones  are often preferred over the sulfonylureas). [ citation needed ]


According to data from Saxony, Germany, MODY was responsible for 2.4% of diabetes incidence in children younger than 15 years. [ 21 ]


The term MODY dates back to 1964, when diabetes mellitus was considered to have two main forms: juvenile-onset and maturity-onset, which roughly corresponded to what we now call type 1 and type 2. MODY was originally applied to any child or young adult who had persistent, asymptomatic  hyperglycemia  without progression to  diabetic ketosis  or  ketoacidosis . In retrospect we can now recognize that this category covered a heterogeneous collection of disorders which included cases of dominantly inherited diabetes (the topic of this article, still called MODY today), as well as cases of what we would now call type 2 diabetes occurring in childhood or adolescence, and a few even rarer types of hyperglycemia (e.g.,  mitochondrial diabetes  or  mutant insulin ). Many of these patients were treated with  sulfonylureas  with varying degrees of success. [ citation needed ]


The current usage of the term MODY dates from a case report published in 1974. [ 22 ] [ 23 ]


Since the 1990s, as the understanding of the pathophysiology of diabetes has improved, the concept and usage of MODY have become refined and narrower. It is now used as a synonym for dominantly inherited, monogenic defects of insulin secretion occurring at any age, and no longer includes any forms of type 2 diabetes. [ 24 ]


McCune–Albright syndrome  is a complex  genetic disorder  affecting the bone, skin and endocrine systems. It is a  mosaic  disease arising from  somatic   activating mutations  in  GNAS , which encodes  the alpha-subunit  of the G s   heterotrimeric G protein . [ 1 ]


It was first described in 1937 by American pediatrician  Donovan James McCune  and American endocrinologist  Fuller Albright . [ 2 ] [ 3 ] [ 4 ]


McCune–Albright syndrome is suspected when two or more of the following features are present:


Patients may have one or many of these features, which may occur in any combination. As such, the clinical presentation of patients with McCune Albright syndrome varies greatly depending on the disease features. [ 6 ]


Various endocrine diseases may present in McCune–Albright syndrome due to increased hormone production.


Genetically, there is a spontaneous  postzygotic mutation  of the  gene   GNAS , on the long (q) arm of chromosome 20 at position 13.3, which is involved in  G-protein  signaling. [ 14 ]  This mutation, which occurs only in the  mosaic  state, leads to constitutive receptor signaling and inappropriate production of excess  cAMP . [ 15 ]


The mutation that causes McCune–Albright syndrome arises very early during embryogenesis. Because all cases of the syndrome are sporadic, it is believed that the mutation would be lethal if it affected all cells in the embryo. Mutant cells can only survive when they are intermixed with normal cells. [ 16 ]


There are no known risk factors for acquiring McCune–Albright syndrome, and no exposures during pregnancy that are known to either cause or prevent the mutation from occurring. The disease cannot be inherited and occurs equally among all ethnic groups. [ 17 ]


McCune–Albright syndrome has different levels of severity. For example, one child with McCune–Albright syndrome may be entirely healthy, with no outward evidence of bone or endocrine problems, enter puberty at close to the normal age, and have no unusual skin pigmentation. Diagnosis may be made only after decades. In other cases, children are diagnosed in early infancy, show obvious bone disease, and obvious increased endocrine secretions from several glands. [ citation needed ]


All patients with known or suspected McCune–Albright syndrome should undergo a screening evaluation for fibrous dysplasia. [ 18 ]  Nuclear medicine tests such as technetium-99 scintigraphy are the most sensitive way to detect fibrous dysplasia lesions. [ 19 ]


CT scan  of the skull is the most useful test to evaluate craniofacial fibrous dysplasia. Regular hearing and vision screening is recommended. X-rays are usually sufficient to reveal fibrous dysplasia of the appendicular skeleton, but CT and/or MRI scans can reveal microfractures. Regular screening for  scoliosis  should also be undertaken. [ citation needed ]


Patients with known or suspected McCune–Albright syndrome should undergo a screening evaluation for endocrine features.


Precocious puberty  is typically diagnosed based on clinical presentation. A bone age examination should be performed to evaluation for skeletal maturation.  Boys and men should have a screening testicular ultrasound. [ 18 ]


Hyperthyroidism  is diagnosed based on blood tests. A screening thyroid ultrasound exam may be performed. [ 18 ]


Growth hormone excess is diagnosed using blood tests, such as insulin-like growth factor-1 levels. Monitoring growth rates alone is not sufficient to screen for growth hormone excess, because linear growth in children with McCune–Albright syndrome may be affected by skeletal deformities and other endocrinopathies. [ 18 ]


Hypophosphatemia is diagnosed by blood phosphorus levels. [ 18 ]


Cushing syndrome is very rare, and is typically diagnosed clinically in infants who present with signs of severe illness. [ 18 ]


Treatment is dictated by both the tissues affected and the extent to which they are affected. [ 17 ]


Surgical management of skeletal abnormalities has evolved over the years. Surgical intervention may be necessary for some skeletal abnormalities.  Bisphosphonates  are helpful in relieving bone pain, but it is no longer believed that they prevent progression of the disease. [ 20 ]   Denosumab  has been found successful in reducing bone pain and decreasing tumor growth, however there is limited safety data available in patients with fibrous dysplasia. [ 21 ]  Muscle strengthening exercises are important for preventing bone fractures; cycling and swimming are recommended in order to reduce the risk of fracture during exercise. [ 17 ]


Screening and management of endocrinopathies is an important part of managing fibrous dysplasia. For example, untreated growth hormone excess increases the risk of craniofacial fibrous dysplasia expansion and may lead to vision loss. [ 22 ]  Untreated hyperthyroidism and hypophosphatemia increases the risk of fractures and skeletal deformities. [ 6 ]


For treatment of precocious puberty, the aromatase inhibitor such as  letrozole  is effective at prevent bleeding episodes and preventing short stature. [ 7 ]  In boys, these should be combined with drugs such as  spironolactone  and  flutamide  to treat androgen excess. [ 23 ]  Periodic ultrasounds of testicular lesions should be performed to screen for cancer. [ 23 ]


Hyperthyroidism is managed with medications such as  thioamides . [ 24 ]  However, because hyperthyroidism in McCune–Albright syndrome does not resolve, surgery or radiation are more definitive treatments. Periodic thyroid examination should be performed to screen for thyroid cancer. [ 18 ]


Oral phosphate and  calcitriol  may be given for treatment of hypophosphatemia. [ 18 ]


For growth hormone excess, treatment with  somatostatin  analogues or  pegvisomant  may be effective. [ 22 ]  Surgery may be an option, but may be complicated by the cranial abnormalities associated with the disorder. Excessive prolactin secretion may also occur; this is treated with dopamine agonists such as  cabergoline . Radiation therapy has been associated with malignant transformation of skull base fibrous dysplasia, and should be avoided in all but the most dire cases. [ 6 ]


Cushing syndrome  is a rare but potentially fatal complication that can occur in the first year of life.  Adrenalectomy  is the treatment of choice.  Metyrapone  may also be used for treatment. [ 17 ]


McCune–Albright syndrome is estimated to occur at a frequency between 1 person in 100,000 to 1 person in 1,000,000 individuals worldwide. [ 25 ]


MDP syndrome , also known as  mandibular   dysplasia  with  deafness  and  progeroid  features, is an extremely rare  metabolic disorder  that prevents fatty tissue from being stored underneath the skin. It is only known to affect a very small number of people worldwide (fewer than 12 cases have been diagnosed as of December 2014). Recent research has suggested that it may be caused by an abnormality of the  POLD1  gene on chromosome 19, which causes an enzyme crucial to DNA replication to be defective.


Initially all people that have been identified with this syndrome have an identical genetic change, an inframe single codon deletion in POLD1 resulting in a loss of  serine  at position 605. [ 1 ]  The POLD1 gene is expressed in all cells and the particular change seen in most patients results in loss of DNA polymerase activity but only mildly impairs the proof reading exonuclease activity. In 2014 a second genetic change was reported in an Italian patient, a novel heterozygous mutation in exon 13 (R507C). [ 2 ]


Most cases identified to date [ when? ]  have been caused by a spontaneous genetic change (so the parents of the individual are unaffected). [ citation needed ]


The diagnosis of MDP syndrome is suggested by the clinical features. [ 3 ]  It can be confirmed by finding a mutation in the POLD1 gene, a service offered by the  molecular genetics  team at the  Royal Devon and Exeter NHS Foundation Trust  /  Exeter University  who originally discovered the genetic cause. [ citation needed ]


Appearance at birth and during the early years is normal but features become more prominent during later childhood prior to puberty. The main issues appear to be lipodystrophy (see below) and slow growth of cartilage and ligaments. The slow growth of cartilage and ligaments results in a small nose, small mandible (jaw), small ears and tightening of ligaments in the limbs. A small larynx (due to
the reduced growth of cartilage) can mean the voice is likely to remain high pitched (even in boys after puberty). [ citation needed ]


A major feature is  lipodystrophy  (a reduction in fat under the skin). The characteristic changes in facial appearance occur from the loss of fat from the cheeks, and around the eyes. Dry eyes and the failure to close eyes during sleep can be a feature due to the loss of fat around the eyes (rather than any excessive prominence of the eyeballs). Limbs appear very thin due to lack of fat storage and also reduced muscle mass. There is a large amount of fat within the abdominal cavity which, can be particularly marked in the liver (but not always) and surrounds the other organs. A major result of the lipodystrophy in some people is severe insulin resistance so insulin does not work very well leading to diabetes and high triglyceride levels in the blood. The effect of insulin resistance can be variable and may relate to progression of the lipodystrophy or may reflect variation between individuals. [ citation needed ]


The skin has a lack of fat and fibrosis. These in turn result in the tight skin on the face and limbs. One direct feature of the lipodystrophy is that the skin is fragile and there is not the protection normally provided by fat under the skin. [ citation needed ]


As fat cannot be stored under the skin it is important to have a healthy diet without excess fat. Often due to failure to thrive or lack of subcutaneous fat there may have been encouragement to add supplements or fat to the diet however this will not result in any increase in fat under the skin and can easily result in it going into tissues such as the liver or kidney where it is not desired. In people with moderate / severe lipodystrophy a low fat diet would be recommended but in those where the lipodystrophy has not progressed (for example in younger children) a healthy relatively low fat diet may be sufficient. The fat and muscle reduction is not the result of dietary insufficiency and cannot be treated with dietary measures. Apart from diet the other thing that is important is exercise which should be encouraged and will make insulin work more effectively. [ citation needed ]


In those who have not developed diabetes it is recommended fasting insulin, triglycerides, glucose and HbA1c should be measured annually to monitor insulin resistance and blood glucose. [ citation needed ]


In those with diabetes it is suggested using  metformin  in doses of at least 2g/day as it decreases insulin resistance and improves insulin sensitivity, following appropriate clinical consultation. [ citation needed ]


The thin skin means if there is trauma there should be rapid attention to any wounds to avoid infection and help primary healing as there can be problems with skin ulcers. [ citation needed ]


Some males have had  undescended testes  but in all cases, whether or not this was corrected, they have  hypogonadism  (reduced function of the testes) and many may be infertile due to inadequate testicular development. In females normal periods have been observed. Low testosterone will require  testosterone replacement . In peri-pubertal males, adequate testosterone replacement is required for its anabolic affects such as growth and also the induction of puberty with high doses. This needs to be coordinated with growth hormone replacement (if given) to avoid early closure of the epitheses (ends of the bones) which would reduce height. [ citation needed ]


Although in the original clinical description short stature was included in the characteristics of MDP syndrome, looking at the data closely it showed that many patients were well within the normal range. If growth is of concern growth hormone therapy could be considered and coordinated with testosterone replacement where appropriate. [ citation needed ]


Deafness is a feature of MDP syndrome as a result of the nerves not working well and people often have difficulty getting hearing aids because of the small size of their ears. Digital hearing aids can be helpful and  audiometry  follow up will be needed. [ citation needed ]


There may be different problems associated with MDP syndrome in the feet. The lack of subcutaneous fat means that there is direct pressure on the skin resulting in callus (hard skin) on the heels and also the weight-bearing parts of the forefoot. This is best managed by trying to find insoles to support the foot but it's difficult to avoid completely. There is no approach that will increase the subcutaneous fat. The second feature is clawed toes as a result of contraction of the long extender tendons. The contractured constrictions can get worse over time. It is worth considering a physiotherapy referral with an aim to establish exercises to try to keep the tendons stretched if possible. [ citation needed ]


The failure of growth of the mandible (lower jaw) can rapidly result in dental overcrowding. In this case it is best to remove teeth early rather than hoping that there will be mandibular (lower jaw) growth. Overcrowding can result in the teeth being severely displaced and again it is best to act early because later correction orthodontically can be extremely difficult. [ citation needed ]


Many people with MDP syndrome are high achievers intellectually following careers in law, medicine and computing. A crucial point is that they do not have  progeria  and there is no evidence of accelerated intellectual decline with age in these patients. Equally life expectancy has not been shown to be reduced. Patients of 65 have been described in the literature and none of the patients are known to have malignancy. Therefore, there are many crucial differences with progeria and the name of  progeroid  in the title is confusing as this really refers to the lack of fat in the face and taut skin and not any intellectual or other age associated features. [ citation needed ]


It is helpful to co-ordinate clinical care as much as possible, this may be managed best by a consultant endocrinologist as the most active management is going to relate to the management of lipodystrophy, insulin resistance, diabetes and testosterone replacement therapy and growth hormone replacement if required. Other local specialists could provide care when this is needed. [ citation needed ]


The condition was diagnosed by researchers at the  University of Exeter Medical School  and Molecular Genetics Department at the  Royal Devon and Exeter Hospital . [ citation needed ]


British para-cyclist  Tom Staniford  is reported to have this condition. [ 4 ] [ 5 ] [ 6 ] [ 7 ]


Meningohydroencephalocoele  ( AmE : meningohydroencephalocele) is a form of  meningocele  ( AmE )—a  developmental abnormality  of the central nervous system. [ citation needed ]


Like meningocoele, meningohydroencephalocoele is caused by defects in bone ossification; in particular, the intramembranous  ossification  related to the closure of infantile  fontanelles . It refers to the protrusion of the  meninges  between the un-fused bones, to lie subcutaneously. [ citation needed ]


Encephalocoele defects occur in approximately 1 in 2000 live births. [ 1 ]


This article about a medical condition affecting the nervous system is a  stub . You can help Wikipedia by  expanding it .


Meromelia  is a  birth defect  characterized by the lacking of a part, but not all, of one or more limbs with the presence of a hand or foot. It results in a shrunken and deformed extremity. [ 1 ]


Such defects are mainly the results of  genetic disorders , but some  teratogenic  (or environmental) factors have been identified, such as the use of  thalidomide  from 1957 to 1962 for  morning sickness  (NVP). [ 1 ]


Meromelia is a birth defect characterized by lacking part of at least one free limb. [ 2 ]


Approximately 0.00001.4% of live births result in meromelia. [ 3 ]


The word  meromelia  comes from the Greek  meros  'part, partial' +  melia  'limb'. [ 4 ]


Michels syndrome  is a  syndrome  characterised by  intellectual disability ,  craniosynostosis ,  blepharophimosis ,  ptosis ,  epicanthus inversus , [ 2 ] [ 3 ]  highly arched  eyebrows , and  hypertelorism . [ 3 ] [ 4 ]  People with Michels syndrome vary in other symptoms such as asymmetry of the  skull ,  eyelid , and  anterior chamber  anomalies,  cleft lip and palate ,  umbilical anomalies , and  growth  and  cognitive development . [ 3 ] [ 4 ]


Miller–Dieker syndrome , also called  Miller–Dieker lissencephaly syndrome  (MDLS) or  chromosome 17p13.3 deletion syndrome , [ 1 ]  is a  micro deletion syndrome  characterized by  congenital malformations . Congenital malformations are physical defects detectable in an infant at birth which can involve many different parts of the body, including the brain, heart, lungs, liver, bones, or intestinal tract.
MDS is a contiguous gene syndrome – a disorder due to the deletion of multiple gene loci adjacent to one another. The disorder arises from the  deletion  of part of the small arm of chromosome 17p (which includes both the  LIS1  and  14-3-3 epsilon  genes), leading to partial  monosomy . There may be unbalanced  translocations  (e.g., 17q:17p or 12q:17p), or the presence of a  ring chromosome  17.


This syndrome is unrelated to  Miller syndrome , a rare genetic disorder, or  Miller Fisher syndrome , a form of  Guillain–Barré syndrome .


The brain is abnormally smooth, with fewer folds and grooves. The face, especially in children, has distinct characteristics including a short nose with upturned nares, thickened upper lip with a thin vermilion upper border, frontal bossing, small jaw, low-set posteriorly rotated ears, sunken appearance in the middle of the face, and  hypertelorism  of eyes. The forehead is prominent with bitemporal hollowing. [ 2 ]  Children typically also have  microcephaly , a wide upper lip, and midface  hypoplasia . [ 3 ]


Characteristics that are not visual include  intellectual disabilities , pre- and postnatal growth retardation,  epilepsy , and reduced lifespan. Children may also experience breathing problems,  dysphagia , feeding problems,  hypotonia ,  spasticity , and muscle stiffness. [ 3 ]   Failure to thrive , feeding difficulties,  seizures  and decreased spontaneous activity are often seen.  Death  usually occurs in  infancy  and childhood.
Multiple abnormalities of the brain, kidneys, and gastrointestinal tract (the stomach and intestines) may occur. [ citation needed ]


MDS is a microdeletion syndrome involving loss of the gene  PAFAH1B1  on  chromosome 17  which is responsible for the syndrome's characteristic sign of  lissencephaly . The loss of another gene,  YWHAE , in the same region of chromosome 17 increases the severity of the lissencephaly in patients with Miller–Dieker syndrome. Additional genes in the deleted region are likely to contribute to the varied features of Miller–Dieker syndrome. [ 4 ]


It may be a random event during the formation of reproductive cells or in early fetal development or due to familial chromosomal rearrangement called chromosomal translocation. In less than 20% of cases an unaffected parent carries a particular chromosomal rearrangement called a  balanced translocation , in which no genetic material is gained or lost. Increased rate of unexplained fetal loss may be observed in those who have these suspectible balanced translocations although they may be otherwise asymptomatic. [ 5 ]  However, these translocations can become also unbalanced as they are passed to the next generation. Miller–Dieker syndrome is usually not inherited. The deletion event occurs randomly during gametogenesis (formation of eggs or sperm) or in early foetal development. [ citation needed ]  Therefore, no history of the disorder is usually seen in their families. [ citation needed ]


The disease may be diagnosed by cytogenetic techniques like  fluorescence in situ hybridization  (FISH), testing for a  microdeletion  at LIS1. [ 6 ]


With the use of prenatal ultrasonographic imaging, early detection of abnormal brain development in the fetus with MDS can be seen. At birth, facial dysmorphism can be present in the infant. Young children, when affected, can have feeding difficulties, severe intellectual disability, developmental delay, and seizures. MRI facilitates early detection of this syndrome in children by revealing a "smooth brain" image, also called lissencephaly. [ 7 ]
Children with this syndrome may remain underdiagnosed because of rarity and the prevalence of facial features that appear to be dysmorphic. The syndrome shares distinct external features ( phenotype ) similar to more common syndromes. Lack of relevant family history may delay diagnosis.
FDNA provides a service that in turn increases the chances of detecting these distinct characteristics, which, when shown to a geneticist, can assist in reaching the right medical diagnosis.
If a couple has had one child with MDS, they can be offered prenatal screening in future pregnancies. This option is particularly important for the few (less than 20%) MDS families where one parent carries a balanced chromosome rearrangement. The risk of these couples having another child with MDS depends on the exact type of chromosomal rearrangement present and may be as high as 25–33%. For families in which both parents' chromosomes are normal, the risk of having another child with MDS is low (1% or less). Either chorionic villus sampling (CVS) or amniocentesis can be used early in a pregnancy to obtain a small sample of cells from the developing embryo for chromosome studies. Early prenatal diagnosis by ultrasound is not reliable because the brain is normally smooth until later in pregnancy. Couples who are considering prenatal diagnosis are usually advised to discuss the risks and benefits of this type of testing with a geneticist or genetic counselor. [ citation needed ]


The brain is usually grossly abnormal in outline when someone is diagnosed with Miller–Dieker syndrome. Only a few shallow sulci and shallow Sylvian fissures are seen; this takes on an hourglass or figure-8 appearance on the axial imaging. The thickness and measurement for a person without MDS is 3–4 mm. With MDS, a person's cortex is measured at 12–20 mm. [ citation needed ]


While no cure for MDS is available yet, many complications associated with this condition can be treated, and a great deal can be done to support or compensate for functional disabilities. Because of the diversity of the symptoms, it can be necessary to see a number of different specialists and undergo various examinations, including: [ citation needed ]


This disease is fairly uncommon, and treatment is scarce.


Most individuals with this condition do not survive beyond childhood. Individuals with MDS usually die in infancy and therefore do not live to the age where they can reproduce and transmit MDS to their offspring.
Due to more accurate diagnosis by  MRI  and improved management of symptoms with medical treatments including  gastrostomy  (feeding tubes), suction machines,  seizure  medications,  tracheostomy , and management of secretions, more children are surviving into adulthood and have a better quality of life. Development of skills and core strength may be improved with physical therapy, but improvement is limited by the severity of the condition. Some children may be able to sit up, crawl, or say a few basic words, but most are severely developmentally delayed and remain at the level of infants for their lifetime.  At all ages the most common cause of death is pneumonia, often after multiple cases have weakened the respiratory function. [ 4 ]


Miller-Dieker occurs in less than one in 100,000 people and can occur in all races. [ citation needed ]
Given this statistic, it is conclusive that roughly 75000 people worldwide are affected by MDS. [ citation needed ]


MDS was named for the two physicians,  James Q. Miller [ 8 ]  and H. Dieker., [ 9 ]  who independently described the condition in the 1960s. The hallmark of MDS is lissencephaly, a condition in which the outer layer of the brain, the cerebral cortex, is abnormally thick and lacks the normal convolutions (gyri). In some areas of the brain, gyri are fewer in number but wider than normal (pachygyri). Other areas lack gyri entirely (agyri). Normally, during the third and fourth months of pregnancy, the brain cells in the baby multiply and move to the surface of the brain to form the cortex. Lissencephaly is caused by a failure of this nerve cell migration. MDS is often called Miller-Dieker lissencephaly syndrome. [ citation needed ]


JQ Miller described the disease and in 1969 H Dieker emphasized that it should also take the name lissencephaly syndrome because several malformations occur beyond the brain itself. When MDS was initially described, geneticists assumed it followed an autosomal recessive pattern of inheritance. In the early 1990s, several patients with Miller–Dieker syndrome were found to be missing a small portion of chromosome 17. (17p13.3) (a partial deletion). [ citation needed ]


Minor physical anomalies  ( MPA s) are relatively minor (typically painless and, in themselves, harmless)  congenital physical abnormalities  consisting of features such as  low-set ears ,  single transverse palmar crease ,  telecanthus ,  micrognathism ,  macrocephaly ,  hypotonia  and  furrowed tongue . While MPAs may have a genetic basis, they might also be caused by factors in the fetal environment:  anoxia , bleeding, or  infection . MPAs have been linked to disorders of  pregnancy  and are thought by some to be a marker for insults to the fetal neural development towards the end of the first trimester. Thus, in the neurodevelopmental literature, they are seen as indirect indications of interferences with  brain development .


MPAs have been studied in  autism ,  Down syndrome , and in  schizophrenia . A 2008  meta-analysis  found that MPAs are significantly increased in the autistic population. [ 1 ]  A 1998 study found that 60% of its schizophrenic sample and 38% of their siblings had 6 or more MPAs (especially in the  craniofacial  area), while only 5% of the control group showed that many. [ 2 ]


The most often cited MPA,  high arched palate , is described in articles as a microform of a  cleft palate . [ 3 ]  Cleft palates are partly attributable to hypoxia. [ 4 ]  The vaulted palate caused by nasal obstruction and consequent mouth breathing, without the lateralising effect of the tongue, can produce  hypoxia  at night. [ citation needed ]


Other MPAs are reported only sporadically. Capillary malformation is induced by RASA1 mutation and can be changed by hypoxia. [ 5 ]   A study in the  American Journal of Psychiatry  by Trixler et al.: [ 6 ]  found hemangiomas to be highly significant in schizophrenia.  Exotropia  is reported as having low correlation and high significance as well. [ 7 ]   It can be caused by perinatal hypoxia. [ 8 ]


Mirror polydactyly-vertebral segmentation-limb defects syndrome  is a very rare  genetic disorder  which is characterized by bilateral symmetrical ( mirror )  polydactyly , vertebral anomalies and diverse limb deficiencies. [ 1 ]  It has been described in four un-related patients from  Spain , which were brought to medical attention by a program called  Spanish Collaborative Study of Congenital Malformations . [ 2 ] [ 3 ]


A  monstrous birth , variously defined in history, is a birth in which a  defect  renders the animal or human child malformed to such a degree as to be considered  "monstrous" . Such births were often taken as  omens , signs of God, or moral warnings to be wielded by society at large as a tool for manipulation in various ways. The development of the field of  obstetrics  helped do away with spurious associations with evil but the historical significance of these  fetuses  remains noteworthy. In  early  and  medieval Christianity , monstrous births were presented as and used to pose difficult  theological  problems about humanity and  salvation .


An early reference to monstrous birth is found in the apocryphal biblical text  2 Esdras , where it is linked to  menstruation : "women in their uncleanness will bear monsters." [ 1 ]  Monstrous births are often placed in a religious context and interpreted as signs and symbols, as is evidenced in the 1493  Nuremberg Chronicle . According to  David Hume 's  "The Natural History of Religion" , they are among the first signs that arouse the barbarian's interest. [ 2 ]  Monstrous human births raise the question of the difference between humans and animals, and anthropologists have described different interpretations of and behaviors toward such births. Among the East African  Nuer people , monstrous births are acted on in a way that restores the division between the categories of human and animal: "the Nuer treat monstrous births as baby hippopotamuses, accidentally born to humans, and, with this labelling, the appropriate action is clear. They gently lay them in the river where they belong." [ 3 ]


Whether monstrous births were natural, unnatural, or supernatural remained a topic of discussion.  Saint Augustine  held that nothing "done by the will of God could be contrary to nature," whereas  Thomas Aquinas  considered some miracles to be against nature. [ 4 ]


Reasons for monstrous births given in early medieval  penitentials  (concerned with sexual sin) and thirteenth-century medical texts (concerned with physical purity) include pollution through  menses  and intercourse during menstruation. [ 5 ]  Such explanations are found in many medieval literary texts, including Jean Maillart's fourteenth-century  Roman du Comte Anjou  and  Geoffrey Chaucer 's " Man of Law's Tale ." [ 6 ]


Sixteenth- and seventeenth-century medical texts, which treat  pregnancy  as a disease, [ 7 ]  suggest that monstrous births may be the result of the mother's sickness or distress, and they continue the myth of (bestial) intercourse during pregnancy as a cause. [ 8 ]  The mother's role is of the greatest importance, and what was presupposed was the possibility of an emotional transference from mother to fetus, referred to as the "theory of the maternal imagination":


According to most of the authors of the sixteenth through early eighteenth centuries, an expectant mother's cravings, desires, and experiences--especially experiences that aroused strong passions such as fear and lust--were capable of  directly  inscribing themselves upon the body of the fetus, producing deformities and monstrosities that retained the semantic content of the original impression. [ 8 ]


At the same time, an epistemological shift was taking place, and monstrous births changed from "signs to facts." Such births were now often publicized in pamphlets and broadsides and became the subject of scientific investigation; the early sixteenth century produced an "apparent upsurge of interest in monstrous births." [ 9 ]


Monstrous animal births often figure in times of religious upheaval. Many occurred in the Europe of the Reformation: the advent of Luther was supposedly announced by the 1522 birth of a monstrous calf (a  mooncalf ) in Saxony, [ 10 ]  and the accession of  Elizabeth I of England  was supposedly indicated by monstrous births as well, as a warning to "Catholics and other sinners." [ 11 ]