An Egyptian family with H syndrome due to a novel mutation inSLC29A3illustrating overlapping features with pigmented hypertrichotic dermatosis with insulin-dependent diabetes and Faisalabad histiocytosis

Abstract

The SLC29A3 gene, encoding hENT3, a member of the equilibrative nucleoside transporter family, has recently been found mutated in Faisalabad histiocytosis, pigmented hypertrichotic dermatosis with insulin-dependent diabetes, familial sinus histiocytosis with massive lymphadenopathy (SHML), and H syndromes. We here report clinical and genetic findings of an Egyptian family with H syndrome. We describe two siblings, a 19-yr old girl and a 15-yr old boy, of consanguineous parents. From 5 yr of age, the girl developed bilateral flexion deformity of interphalengeal joints and insulin-dependent diabetes mellitus. At age 7 yr, prominent hyperpigmented patches appeared on the skin at lower limbs, genitalia, and trunk. On clinical examination, she had hepatosplenomegaly, generalized lymphadenopathy, left ventricular hypertrophy, sensorineural hearing loss, hypogonadism, short stature, and characteristic dysmorphic features. Her brother had fixed flexion contractures of the feet, profound sensorineural hearing loss, characteristic dysmorphic features, but no diabetes. DNA sequence analysis revealed a homozygous mutation (c.300+1G>C) in SLC29A3 in both siblings. The phenotype and genotype of the siblings were compatible with that of the H syndrome, although the features were overlapping with those found in pigmented hypertrichotic dermatosis with insulin-dependent diabetes, familial SHML, and Faisalabad histiocytosis, indicating that these four syndromes may be regarded as one disease with varying phenotypic features. A new, common name for these conditions is warranted.

The histopathology and phenotypic variability in H syndrome

“…Phenotypic variability in H syndrome further emphasizes the need for diagnostic measures. The c.G1309>A mutation has been associated with multiple abnormalities including short stature, exophthalmos, dilated lateral scleral vasculature, hearing loss, congenital cardiac anomalies, hepatomegaly, hypogonadism, varicose veins, fixed flexion, hallux valgus, flat foot, malabsorption, and hyperglycemia 1, 6, 7, 8, 9, 10, 11, 12. Our patient had only hearing loss, a prominent feature of this syndrome 8.…”

Compound heterozygous SLC29A3 mutation causes H syndrome in a Moroccan patient: A case report

“…The splice site mutation c.300+1G>C (p.N101LfsX34), is predicted to abolish the splice donor site of exon 2, leading to a premature termination, resulting in a truncated protein. This mutation was previously reported in a Moroccan girl [7] and in two Egyptian siblings [8] with overlapping features of pigmented hypertrichotic dermatosis with insulin-dependent diabetes, Faisalabad histiocytosis and H syndrome. It's important to note that these three patients presented the most extreme clinical features identified to date in patients with SLC29A3 mutations such as hyperpigmentation, insulin-dependent diabetes, cardiac anomalies, hearing loss, arthrogryposis and anaemia with erythroblastopenia.…”

Pigmentary hypertrichosis and non-autoimmune insulin-dependent diabetes mellitus (PHID) syndrome is associated with severe chronic inflammation and cardiomyopathy, and represents a new monogenic autoinflammatory syndrome

“…The amyloidoses represent a group of clinical disorders of diverse etiologies that have as a common pathophysiologic denominator the deposition of misfolded protein-based amyloid fibrils in the interstitial space of various organs (10). Although the features in our patient are not typical of cardiac amyloidosis, the (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). The images are captured in series, 12 min after a bolus dose of gadolinium.…”

“…Diabetes mellitus is observed at a very high frequency in the PHID cohort, whereas deafness is more common in H syndrome (3). However, overlapping features of both syndromes have been reported in the same patient (6,9). The pathognomonic feature of both syndromes is the presence of distinctive hyperpigmented, hypertrichotic indurated cutaneous patches and plaques with an underlying inflammatory cell infiltrate (6).…”