Atypical Hypotonia-Cystinuria a New Case: Genotype-Phenotype, Description

Hypotonia-Cystinuria syndrome (HCS; OMIM 606407) is a rare syndrome including neonatal and infantile hypotonia and failure to thrive, cystinuria type 1 and nephrolithiasis, growth retardation due to growth hormone deficiency, and minor facial dysmorphism. Hypotonia-cystinuria syndrome is the presence of cystinuria type I (disruption on the SLC3A1 locus at chromosome 2p21), recessive deletions in contiguous genes in the same chromosome result in variable phenotypes depending on the different size and number of the deleted genes involved. HCS patients, only SLC3A1 and PREPL genes are disrupted, whereas in the 2p21 deletion syndrome, two additional genes (C2orf34 and PM1B) are deleted.

The HCS syndrome is characterized by generalized hypotonia at birth while failure to thrive, and severe growth retardation due to growth hormone deficiency, characteristic facial dysmorphy and cystinuria type 1 appear later in childhood. As mutations in SLC3A1 cause isolated cystinuria type 1, the extended phenotype can be attributed to PREPL.The recent advances in medical technology give more insight into the four genes involved in the contiguous deletion syndromes at the 2p21 locus (SLC3A1, PREPL, CAMKMT and PPM1B) associated with cystinuria.

In summary, a new patient is reported to be carrying a homozygous deletion in the 2p21 region, including three genes: SLC3A1, PREPL and C2orf34. In the first two families described with aHCS, both of which had two children affected, the same phenotype has been reported.

Our case, in association with the recent literature, further elucidates the complex genotype-phenotype correlations of the contiguous deletion syndromes associated with cystinuria. The phenotypic refinement reported in this paper together with the new screening tool for PREPL deficiency and the progress of medical genetics with the array CGH in pre- and post-natal settings make nowadays a reliable diagnosis of contiguous deletion syndromes feasible.

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