Novel homozygous SLC29A3 mutations among two unrelated Egyptian families with spectral features of H-syndrome.

OBJECTIVES: H syndrome and pigmented hypertrichosis with insulin-dependent diabetes mellitus (PHID) had been described as two autosomal recessive disorders. We aim to screen for pathogenic SLC29A3 mutations in two unrelated Egyptian families with affected siblings of these overlapping syndromes. METHODS: Clinical, laboratory, histopathological, and radiological characteristics of individuals probably diagnosed as H and/or PHID syndrome were reported. Mutation analysis of SLC29A3 gene was performed for all members of the two Egyptian families. RESULTS: All affected individuals were females; proband of family-I (A1961) displayed overlapping features of H syndrome and PHID, while her younger brother (A1962) was asymptomatic. A1961 presented with previously undescribed features; absent pectoralis major muscle and a supracondylar bony spur in left humerus. In family-II, probands (A1965 and A1966) had clinical features consistent with classical H syndrome with unique early onset of cutaneous phenomena at birth. Mutation analysis of SLC29A3 revealed homozygous mutation previously reported in literature c.1279G>A [p.G427S] in A1961 and unexpectedly in the asymptomatic A1962 of family-I. Probands of family-II were homozygous for a novel mutation c.401G>A [p.R134H], in the same codon that was published in an Indian boy [p.R134C]. CONCLUSIONS: We emphasize the inter- and intra-familial genetic heterogeneity among Egyptian patients with overlapping features of SLC29A3 disorders. This suggests the presence of other factors like regulatory genes or epigenetic factors that may explain variable disease manifestations and severity.

Sporadic Fibrodysplasia Ossificans Progressiva in an Egyptian Infant with c.617G > A Mutation in ACVR1 Gene: A Case Report and Review of Literature.

Fibrodysplasia ossificans progressiva (FOP) is an autosomal dominant severe musculoskeletal disease characterized by extensive new bone formation within soft connective tissues and unique skeletal malformations of the big toes which represent a birth hallmark for the disease. Most of the isolated classic cases of FOP showed heterozygous mutation in the ACVR1 gene on chromosome 2q23 that encodes a bone morphogenetic protein BMP (ALK2). The most common mutation is (c.617G > A) leading to the amino acid substitution of arginine by histidine (p.Arg206His). We currently report on an Egyptian infant with a sporadic classic FOP in whom c.617G > A mutation had been documented. The patient presented with the unique congenital malformation of big toe and radiological evidence of heterotopic ossification in the back muscles. The triggering trauma was related to the infant's head, however; neither neck region nor sites of routine intramuscular vaccination given during the first year showed any ossifications. Characterization of the big toe malformation is detailed to serve as an early diagnostic marker for this rare disabling disease.

A novel homozygous p.Arg527Leu LMNA mutation in two unrelated Egyptian families causes overlapping mandibuloacral dysplasia and progeria syndrome.

Mandibuloacral dysplasia (MAD) is a rare disease resulting from a mutation of LMNA gene encoding lamins A and C. The most common mutation associated with this disease is a homozygous arginine 527 replacement by histidine. Three female patients originating from two unrelated families from Northeast Egypt were examined. Their growth was retarded; they had microcephaly, widened cranial sutures, prominent eyes and cheeks, micrognathia, dental crowding, hypoplastic mandible, acro-osteolysis of distal phalanges, and joint contractures. In addition, they presented some progeroid features, such as pinched nose, premature loss of teeth, loss of hair, scleroderma-like skin atrophy, spine rigidity, and waddling gait. The clinical presentation of the disease varied between the patient originating from Family 1 and patients from Family 2, suggesting that unknown, possibly epigenetic factors, modify the course of the disease. The first symptoms of the disease appeared at the age of 2.5 (a girl from Family 1), 5, and 3 years (girls from Family 2). All patients had the same, novel homozygous c.1580G>T LMNA mutation, resulting in the replacement of arginine 527 by leucine. Computational predictions of such substitution effects suggested that it might alter protein stability and increase the tendency for protein aggregation, and as a result, might influence its interaction with other proteins. In addition, restriction fragment-length polymorphism analysis performed in 178 unrelated individuals showed that up to 1.12% of inhabitants of Northeast Egypt might be heterozygous carriers of this mutation, suggesting the presence of a founder effect in this area.

p.R672C mutation of MYH3 gene in an Egyptian infant presented with Freeman-Sheldon syndrome.

OBJECTIVE: To define the mutation type in a clinically suspected Egyptian child with Freeman-Sheldon syndrome (FSS); it involves certain skeletal malformations with some facial characteristics; skeletal malformations include camptodactyly with ulnar deviation, talipes equinovarus, while the facial characteristics include deep-sunken eyes with hypertelorism, long philtrum, small pinched nose and pursed mouth. METHODS: Amplification of exon 17 of the embryonic myosin heavy chain (MYH3) gene was done using one forward and two different reverse primers, and then the cleaned PCR product was sequenced. RESULT: A de novo missense mutation (c.2014C>T with replacement C > Y) in MYH3 gene leading to change of arginine at position 672 by cytosine in protein sequence. CONCLUSION: Mutation analysis remains to be the standard way for definitive diagnosis in FSS. The authors currently report, for the first time in an Egyptian infant aged 16 months who presented with FSS, a c.2014C>T missense mutation of MYH3 gene, with no family history or consanguinity.