A B3GALT6 variant in patient originally described as Al-Gazali syndrome and implicating the endoplasmic reticulum quality control in the mechanism of some ß3GalT6-pathy mutations.

Al-Gazali syndrome encompasses several clinical features including prenatal growth retardation, large joints contractures with camptodactyly, bilateral talipes equinovarus, small mouth, anterior segment anomalies of the eyes, and early lethality. Recently, a baby with features very similar to Al-Gazali syndrome was found to have compound heterozygous variants in B3GALT6. This gene encodes Beta-1,3-galactosyltransferase 6 (ß3GalT6), an essential component of the glycosaminoglycan synthesis pathway. Pathogenic variants in B3GALT6 have also been shown to cause Ehlers-Danlos syndrome spondylodysplastic type (spEDS-B3GALT6) and spondyloepimetaphyseal dysplasia with joint laxity type I (SEMD-JL1). In 2017, a new international classification of EDS included these 2 conditions together with the child reported to have features similar to Al-Gazali syndrome under spondylodysplastic EDS (spEDS). We report a disease-causing variant c.618C > G, p.(Cys206Trp) in 1 patient originally described as Al-Gazali syndrome and reported in 1999. We evaluated the involvement of the endoplasmic reticulum-associated protein degradation, in the pathogenesis of 13 B3GALT6 variants. Retention in endoplasmic reticulum was evident in 6 of them while the c.618C > G, p.(Cys206Trp) and the other 6 variants trafficked normally. Our findings confirm the involvement of B3GALT6 in the pathogenesis of Al-Gazali syndrome and suggest that Al-Gazali syndrome represents the severe end of the spectrum of the phenotypes caused by pathogenic variants in this gene.

Expanding the clinical and genetic spectra of NKX6-2-related disorder.

Hypomyelinating leukodystrophies (HLDs) affect the white matter of the central nervous system and manifest as neurological disorders. They are genetically heterogeneous. Very recently, biallelic variants in NKX6-2 have been suggested to cause a novel form of autosomal recessive HLD. Using whole-exome or whole-genome sequencing, we identified the previously reported c.196delC and c.487C>G variants in NKX6-2 in 3 and 2 unrelated index cases, respectively; the novel c.608G>A variant was identified in a sixth patient. All variants were homozygous in affected family members only. Our patients share a primary diagnosis of psychomotor delay, and they show spastic quadriparesis, nystagmus and hypotonia. Seizures and dysmorphic features (observed in 2 families each) represent an addition to the phenotype, while developmental regression (observed in 3 families) appears to be a notable and previously underestimated clinical feature. Our findings extend the clinical and mutational spectra associated with this novel form of HLD. Comparative analysis of our 10 patients and the 15 reported previously did, however, not reveal clear evidence for a genotype-phenotype correlation.

Chondrodysplasia with multiple dislocations: comprehensive study of a series of 30 cases.

The group of chondrodysplasia with multiple dislocations includes several entities, characterized by short stature, dislocation of large joints, hand and/or vertebral anomalies. Other features, such as epiphyseal or metaphyseal changes, cleft palate, intellectual disability are also often part of the phenotype. In addition, several conditions with overlapping features are related to this group and broaden the spectrum. The majority of these disorders have been linked to pathogenic variants in genes encoding proteins implicated in the synthesis or sulfation of proteoglycans (PG). In a series of 30 patients with multiple dislocations, we have performed exome sequencing and subsequent targeted analysis of 15 genes, implicated in chondrodysplasia with multiple dislocations, and related conditions. We have identified causative pathogenic variants in 60% of patients (18/30); when a clinical diagnosis was suspected, this was molecularly confirmed in 53% of cases. Forty percent of patients remain without molecular etiology. Pathogenic variants in genes implicated in PG synthesis are of major importance in chondrodysplasia with multiple dislocations and related conditions. The combination of hand features, growth failure severity, radiological aspects of long bones and of vertebrae allowed discrimination among the different conditions. We propose key diagnostic clues to the clinician.

Fibrochondrogenesis: prenatal diagnosis and outcome.

We studied 20 cases with fibrochondrogenesis (FCG) diagnosed prenatally. Four cases were diagnosed at our fetal unit, and 16 cases were identified through a review of literature (in English). The prenatal diagnosis of FCG was made in 4/20 (20%). Six (30%) patients opted for termination of pregnancy (TOP). A total of 13 cases delivered at term. Four (30.8%) had a caesarean section. Four neonates (30.7%) were stillborn and seven (53.8%) neonates died within 3 months. Two infants survived beyond 3 years of age, but both had severe global developmental delay. A molecular study of the surviving children revealed two null homozygous mutations in COL11A1 [c.4084C > T (p.R1362X) and c.3708 + c.437T > G]. We concluded that the prenatal diagnosis of fibrochondrogenesis is feasible. Fibrochondrogenesis is usually a fatal disease and survivors suffer from severe physical and neurological impairment.

Clinical and molecular analysis of UAE fibrochondrogenesis patients expands the phenotype and reveals two COL11A1 homozygous null mutations.

Fibrochondrogenesis is documented to be a neonatally lethal rare recessively inherited disorder characterized by short-limbed skeletal dysplasia. Here we report two patients from two unrelated consanguineous Emirati families who have unexpectedly survived till the ages of 3 and 6 years. These patients show additional symptoms which include developmental delay, profound sensory-neural deafness, severe myopia and progressive severe skeletal abnormalities. Linkage of fibrochondrogenesis in the Emirati families to chromosome 1 has been established using homozygosity mapping confirming recent findings by Tompson et al. in 2010. Screening of the COL11A1 gene revealed two null homozygous mutations [c.4084C>T (p.R1362X) and c.3708+437T>G] in the aforementioned two families. The c.4084C>T mutation is predicted to introduce a stop codon at position Arg1362, whereas the c.3708+437T>G mutation causes the activation of an intronic pseudoexon between exons 48 and 49. This resulted in the insertion of 50 nucleotides into the mRNA. The carriers of these mutations display ocular defects with normal hearing. In conclusion, our data shall improve the overall understanding of fibrochondrogenesis especially in surviving homozygous patients and, at least partly, explain the phenotypic variability associated with COL11A1 gene mutations.

Stüve-Wiedemann syndrome and related bent bone dysplasias.

Stüve-Wiedemann syndrome (SWS) is a severe congenital skeletal dysplasia associated with life threatening dysautonomic manifestations. Newborns affected with this condition exhibit distinctive shortening and bowing of the long bones with reduced bone volume. The majority of affected newborns die early due to neuromuscular complications namely hyperthermia, apnea, and swallowing difficulties. In this review, we provide an overall picture on the clinical, including long-term management, molecular and cellular aspects of SWS and discuss briefly other related bent bone dysplasias.

Stuve-Wiedemann syndrome: a skeletal dysplasia characterized by bowed long bones.

OBJECTIVE: To describe the prenatal sonographic features of Stuve-Wiedemann syndrome (SWS). METHODS: A retrospective review of all cases of confirmed SWS during an 8-year period was conducted. Clinical and historical data and outcome of the pregnancies were noted. Fetal biometry, skeletal survey, amniotic fluid volume and associated anomalies were recorded. A sonographic algorithm was proposed to distinguish SWS from other bent bone disorders. RESULTS: In total, there were 10 cases, six of which were diagnosed prenatally. The main prenatal features of SWS were mild-to-moderate micromelia and bowing of the lower limb bones, affecting the tibia more than the femur. There was relative sparing of fibula and upper limb bones, with normal scapulae and clavicles. Camptodactyly was the main associated anomaly. All fetuses developed growth restriction in the late second trimester with oligohydramnios in half of the cases. These features could appear late in pregnancy. Although the thoracic dimensions were normal in the majority of fetuses, respiratory insufficiency, as a result of myotonia, was a leading cause for mortality. CONCLUSIONS: It is possible to diagnose SWS prenatally. SWS is associated with high mortality during the first year of life, and those who survive have high morbidity.

A new autosomal recessive syndrome of ocular colobomas, ichthyosis, brain malformations and endocrine abnormalities in an inbred Emirati family.

We report on an inbred Emirati family of Baluchi origin with ocular colobomas, ichthyosis, and endocrine abnormalities associated with midline brain malformations and mental retardation. All affected children had ocular colobomas, developmental delay and midline brain malformations. Hypoplastic pituitary gland was present in all three investigated children. Ichthyosiform dermatitis appeared in infancy in all surviving children. Other variable features include congenital heart defects, hypertrichosis and dark skin involving the dorsum of hands and feet associated with mild degree of palmo-plantar keratoderma. Some of the features in this family overlap the CHIME (Coloboma of the eye, Heart defect, Ichthyosiform dermatosis, Mental retardation, and Ear defect) syndrome. However, several features described in CHIME syndrome were not present in these children. These include deafness, seizures, oligodontia, and hair abnormalities. Some of the features in these children also overlap with septo-optic dysplasia (SOD) but optic nerve hypoplasia, mandatory for the diagnosis of SOD, was present in one child only. We suggest that these children have a new autosomal recessive syndrome of ocular colobomas and ichthyosis.

Diagnostic criteria, clinical characteristics, and natural history of Cohen syndrome.

Cohen syndrome is a rare, recessively inherited condition associated with facial dysmorphism, developmental delay, and visual disability. A delay in making the diagnosis commonly occurs, contributed to by the lack of a definitive molecular test and the clinical variability of published case reports. A specific clinical phenotype has been delineated in a homogeneous cohort of Finnish Cohen syndrome patients, but the applicability of their diagnostic criteria to non-Finnish patients has been debated. Detailed delineation of Cohen syndrome in patients from outside Finland is therefore warranted. We report on the clinical features of 33 non-Finnish Cohen syndrome patients. Variability within the clinical spectrum is identified and the natural history of Cohen syndrome described. Diagnostic guidelines for facilitating accurate and early diagnosis are discussed. Results from molecular genetic analysis using markers located within the previously mapped COH1 critical region support allelic but not genetic heterogeneity in this UK cohort.

Homozygosity mapping of a Desbuquois dysplasia locus to chromosome 17q25.3.

Desbuquois dysplasia is a rare autosomal recessive chondrodysplasia characterised by short stature, joint laxity, facial dysmorphism, a "Swedish key" appearance of the proximal femur, advanced carpal and tarsal bone age, and hand anomalies consisting of phalangeal dislocations and an extra ossification centre distal to the second metacarpal. However, the latter changes are not consistently observed in all Desbuquois patients, defining two distinct groups, based on the presence or absence of hand anomalies. We have performed a genome wide search in four inbred Desbuquois families with typical hand anomalies originating from France, Sri-Lanka, the United Arab Emirates, and Morocco. Here, we report on the mapping of a disease gene to chromosome 17q25.3 (Zmax=4.61 at theta=0 at locus D17S1806) in the 9.5 cM interval defined by loci D17S802 and D17S1822. The present study supports the genetic homogeneity of the clinical subtype with hand anomalies and will hopefully help in identifying the Desbuquois dysplasia gene.

Identification of a locus for a form of spondyloepiphyseal dysplasia on chromosome 15q26.1: exclusion of aggrecan as a candidate gene.

We have investigated a family with an autosomal dominant form of spondyloepiphyseal dysplasia (SED) characterised by short stature and severe premature degenerative arthropathy. Previous studies have excluded linkage between this condition and the locus for the type II collagen gene. Here we report the identification of linkage between this disorder and a locus on the long arm of chromosome 15 between markers D15S979 and D15S1004. According to current linkage maps and sequence data, this locus includes that of the aggrecan gene (AGC1). Our linkage data from the SED family show, however, that AGC1 maps to a locus that is proximal to D15S979. This proximal location for AGC1 is further supported by linkage data from a second family with an autosomal recessive form of multiple epiphyseal dysplasia that also maps to the SED locus. In both families AGC1 is therefore excluded as a candidate gene.

Localisation of a gene for an autosomal recessive syndrome of macrocephaly, multiple epiphyseal dysplasia, and distinctive facies to chromosome 15q26.

BACKGROUND: We have previously described an autosomal recessive syndrome of macrocephaly, multiple epiphyseal dysplasia (MED), and distinctive facies in a large, extended Omani family. The MED observed seems to be part of a larger malformation syndrome, since both craniofacial and central nervous system changes were present in the family. We performed a whole genome scan in this family in order to identify the gene locus for this malformation syndrome. METHODS AND RESULTS: Using homozygosity mapping, we show linkage to the telomeric region of the long arm of chromosome 15. The position of both the disease gene and the principal glycoprotein, chondroitin sulphate proteoglycan (aggrecan, AGC1) on chromosome 15q26, suggested that the aggrecan gene is a candidate for the disease in this family. However, three of the four affected children were heterozygous for a polymorphism at position 831 of the coding sequence of AGC1, providing strong evidence against its involvement. CONCLUSION: We have identified a gene locus for a recessive syndrome of macrocephaly, MED, and distinctive facies in a large Omani family. Aggrecan located on chromosome 15q26, within the critical region determined for this syndrome in this family, was excluded as a candidate gene.

A new locus for autosomal recessive non-syndromal sensorineural hearing impairment (DFNB27) on chromosome 2q23-q31.

Non-syndromic sensorineural deafness is an extremely genetically heterogeneous condition. We have used autozygosity mapping in a large consanguineous United Arab Emirate family to identify a novel locus for autosomal recessive non-syndromic sensorineural deafness, DFNB27, on chromosome 2q23-q31, with a maximum two-point lod score of 5.18 at theta = 0 for marker D2S2257. The DFNB27 locus extends over a 17 cM region between D2S2157 and D2S2273, and may overlap the DFNA16 locus for dominantly inherited, fluctuating, progressive non-syndromal hearing loss. However, genotype data suggests that the locus is likely to be refined to between D2S326 and D2S2273 and thus distinct from the DFNA16 locus.

Agyria-pachygyria and agenesis of the corpus callosum: autosomal recessive inheritance with neonatal death.

We report three neonates, one boy and two girls, born to an inbred Arab family who had cortical dysplasia, probably agyria-pachygyria, and agenesis of the corpus callosum. All had asphyxia, intractable seizures, and increased muscle tone at birth and died in the neonatal period. Congenital microcephaly or dysmorphic features were absent. Cytogenetic abnormality, metabolic disorder, and intrauterine infection were excluded. These cases suggest a new cerebral dysgenesis syndrome with autosomal recessive inheritance.

Gerodermia osteodysplastica and wrinkly skin syndrome: are they the same?

Gerodermia osteodysplastica (GO) is a connective tissue disorder characterized by premature aging, wrinkled, and lax skin with reduced elasticity which is more marked on the dorsum of the hands and feet associated with hyperextensible joints and osteoporosis. The wrinkly skin syndrome (WSS) is characterized by wrinkled skin over the dorsum of the hands, feet, and abdomen; hyperextensible joints, particularly of the hands; intrauterine growth retardation; postnatal failure to thrive; and mental and developmental delay. We report on five children from two consanguineous Arab families with features overlapping both GO and WSS. All five children had similar dysmorphic facial features consisting of broad and prominent forehead, hypotelorism with epicanthal folds, prominent bulbous nose, flat malar region, and large protruding ears. All had wrinkling of the skin more marked on the dorsum of the hands, feet, and abdomen; hyperextensibility of the joints, particularly of the hands; and aged appearance. Intrauterine growth retardation, subsequent failure to thrive, developmental delay, and variable degree of osteoporosis was also present in all of them. The older three children developed progressive prognathism. We suggest that GO and WSS could represent variable manifestation of the same disorder.

Severe facial clefting, limbic dermoid, hypoplasia of the corpus callosum, and multiple skin appendages: severe frontofacionasal "dysplasia" or newly recognised syndrome?

We report on a child with severe midline facial cleft, bilateral cleft lip and palate, telecanthus, S-shaped palpebral fissures, limbic dermoid, midface hypoplasia, hypoplastic corpus callosum, and multiple skin appendages. This case may be an example of severe frontofacionasal "dysplasia" or a newly recognised syndrome.

Abnormal folate metabolism and genetic polymorphism of the folate pathway in a child with Down syndrome and neural tube defect.

The association of neural tube defects (NTDs) with Down syndrome (trisomy 21) and altered folate metabolism in both mother and affected offspring provide a unique opportunity for insight into the etiologic role of folate deficiency in these congenital anomalies. We describe here the case of a male child with trisomy 21, cervical meningomyelocele, agenesis of corpus callosum, hydrocephaly, cerebellar herniation into the foramen magnum, and shallow posterior cranial fossa. Molecular analysis of the methylenetetrahydrofolate (MTHFR) gene revealed homozygosity for the mutant 677C-->T polymorphism in both the mother and child. The plasma homocysteine of the mother was highly elevated at 25.0 micromol/L and was associated with a low methionine level of 22.1 micromol/L. Her S-adenosylhomocysteine (SAH) level was three times that of reference normal women, resulting in a markedly reduced ratio of S-adenosylmethionine (SAM) to SAH and significant DNA hypomethylation in lymphocytes. The child had low plasma levels of both homocysteine and methionine and a reduced SAM/SAH ratio that was also associated with lymphocyte DNA hypomethylation. In addition, the child had a five-fold increase in cystathionine level relative to normal children, consistent with over-expression of the cystathionine beta synthase gene present on chromosome 21. We suggest that altered folate status plus homozygous mutation in the MTHFR gene in the mother could promote chromosomal instability and meiotic non-disjunction resulting in trisomy 21. Altered folate status and homozygous TT mutation in the MTHFR gene in both mother and child would be expected to increase the risk of neural tube defects. The presence of both trisomy 21 and postclosure NTD in the same child supports the need for an extended periconceptional period of maternal folate supplementation to achieve greater preventive effects for both NTD and trisomy 21.

Mental health problems among schoolchildren in United Arab Emirates: prevalence and risk factors.

OBJECTIVE: To examine child psychiatric morbidity in an Arab culture. METHOD: Emotional and behavioral problems were investigated in 3,278 schoolchildren aged 6 to 15 years using a two-stage epidemiological study in Al Ain District, United Arab Emirates. Children were screened using standardized questionnaires completed by parents and school physicians in the first stage, and a stratified random sample were interviewed by a child psychiatrist in the second stage. RESULTS: 23.9% of children were reported to have a mental health problem by either the parent or the school health physician. Boys were more often reported to be having problems than girls (1.8:1). Using the Rutter A2 scale for parents, the prevalence estimate for behavioral disorders was 16.5%. The weighted prevalence for DSM-IV disorders was 10.4% for the entire population. The presence of certain culture-specific risk factors such as male gender, number of children in the household, polygamy, and low socioeconomic status were identified for psychiatric disorders. A positive family history and consanguinity were the most significant factors associated with learning disorders. CONCLUSIONS: The prevalence rates of child psychiatric disorders and the symptomatology observed in this Middle East community are similar to those reported in Western studies.

Are the strokes in moyamoya syndrome associated with Down syndrome due to protein C deficiency?

Moyamoya syndrome has occasionally been seen in association with Down syndrome. We report a child with moyamoya syndrome and Down syndrome who was admitted with repeated episodes of strokes; his magnetic resonance imaging and magnetic resonance angiography findings confirmed the presence of occlusive cerebrovascular disease with basal collateral vessels. His protein C levels were significantly decreased during the stroke. Complete clinical recovery was seen during follow-up. This raises the possibility of a link between protein C deficiency and Down syndrome with moyamoya syndrome.