Hypotonia-Cystinuria Syndrome

A number sign (#) is used with this entry because hypotonia-cystinuria syndrome is a contiguous gene syndrome caused by a homozygous deletion on chromosome 2p21 that disrupts the SLC3A1 (104614) and PREPL (609557) genes. The deletion ranges in size from 23.8 to 75.5 kb.

Larger homozygous deletions in this region, including a 179-kb deletion, result in a more severe phenotype termed the '2p21 deletion syndrome.' Genes deleted in the 2p21 deletion syndrome include SLC3A1, PREPL, PPM1B (603770), C2ORF34 (609559), and possibly other genes.

Homozygous mutations in the SLC3A1 gene result in isolated cystinuria (220100), and isolated loss of PREPL results in congenital myasthenic syndrome-22 (CMS22; 616224).

Clinical Features

Parvari et al. (2001) identified 4 male and 3 female patients from an extended, small Bedouin family who presented with an autosomal recessive syndrome consisting of cystinuria as well as neonatal seizures, hypotonia, severe somatic and developmental delay, facial dysmorphism, and lactic acidosis. The patients were born at term with normal growth parameters, but had linear growth impairment and severe failure to thrive. All had moderate to severe mental retardation. Brain CT scans were normal. Dysmorphic facies included frontal bossing, almond-shaped eyes, long eyelashes, depressed nasal bridge, and large, posteriorly rotated ears. Renal and/or bladder cystine calculi were detected in all patients as early as 9 months. Serum lactate level was elevated in 4 of the 7 patients, and studies of muscle biopsies suggested mitochondrial dysfunction.

Jaeken et al. (2006) reported 11 patients from 9 families with hypotonia-cystinuria syndrome. Seven families were Flemish and 2 were French. The clinical features were similar to those reported by Parvari et al. (2001), but were milder. The phenotype was characterized by generalized hypotonia at birth, cystine nephrolithiasis, growth hormone deficiency, minor facial dysmorphism, and failure to thrive, followed by hyperphagia and rapid weight gain in late childhood. Facial dysmorphism included dolichocephaly, ptosis, and tented upper lip. Gross motor development was mildly to moderately retarded, and 3 patients required special education. All patients had nasal speech. Seven patients showed late puberty, 4 with hypergonadotropic hypogonadism. All patients had nephrolithiasis in the first decade. There was no evidence of a mitochondrial disease.

Chabrol et al. (2008) reported a brother and sister, born of unrelated Moroccan parents from the same village, with a phenotype that was intermediate between hypotonia-cystinuria syndrome and the 2p21 deletion syndrome. Both showed neonatal hypotonia with inability to suck, delayed motor development, and later growth delay. The boy had slight craniofacial dysmorphism including dolichocephaly, frontal bossing, mild ptosis of the eyelids, slight epicanthal folds, arched philtrum, and retrognathia. He was lost from follow-up until at the age of 17 years when he showed moderate mental retardation with learning disabilities and episodes of weakness and fatigability. A younger sister showed arthrogryposis, muscular hypotrophy and hypotonia, and absent deep tendon reflexes at birth. At 8 years, she still showed muscular weakness, hypotonia, and obvious mental retardation. Brain MRI showed localized unspecific white matter subcortical signal anomalies and muscle biopsy showed mitochondrial complex IV deficiency. Both patients had at least 1 episode of renal calculus. Two older brothers had died in infancy with severe unexplained hypotonia.

Mapping

By linkage analysis of a Bedouin family with hypotonia-cystinuria syndrome, Parvari et al. (2001) found that the patients were homozygous for the same deletion on chromosome 2p, including the SLC3A1 gene, which was originally reported by the authors as '2p16.' Repeated failures to amplify the 10 exons of the SLC3A1 gene indicated a large deletion in this region.

Parvari et al. (2005) corrected and refined the localization of the deletion in the hypotonia-cystinuria syndrome to chromosome 2p21.

Molecular Genetics

In all affected patients of a Bedouin family with hypotonia-cystinuria syndrome, Parvari et al. (2001) identified a homozygous 179-kb deletion on chromosome 2p, including the SLC3A1, PPM1B, and PREPL genes. All parents were heterozygous for the deletion. The authors suggested that the early age at onset of renal calculi in these patients was compatible with complete deletion of the SLC3A1 gene. The contribution of the other deleted genes to the phenotype could not be established. Parvari et al. (2005) reported the transcription content of the deleted region on 2p21. They determined that the first exon of an additional gene, C2ORF34, was also located within the deleted region. C2ORF34 was not expressed in patients with the 2p21 deletion.

In 11 patients from 9 families with hypotonia-cystinuria syndrome, Jaeken et al. (2006) identified deletions on 2p21 ranging in size from 23.8 kb to 75.5 kb. All had complete deletion of the SLC3A1 gene. Further analysis showed that all patients also had deletion of the PREPL gene, but there was normal expression of the flanking genes C2ORF34 and PPM1B. Jaeken et al. (2006) concluded that the cystinuria was due to deletion of the SLC3A1 gene and that the additional phenotypic features could be attributed to deletion of the PREPL gene.

In 2 Moroccan sibs with atypical hypotonia-cystinuria syndrome, Chabrol et al. (2008) identified a homozygous 77.4-kb deletion of chromosome 2p21, including the SLC3A1, PREPL, and C2ORF34 genes. Atypical clinical features included mild to moderate mental retardation and respiratory chain complex IV deficiency in 1 of the sibs.

Clinical Management

Regal et al. (2014) found that 1 of 3 additional unrelated patients with hypotonia-cystinuria syndrome (HCS) and hypotonia showed a positive response to pyridostigmine; the patient who responded was an infant, whereas the other 2 patients were older children.

Nomenclature

Parvari et al. (2001) originally mapped the deletion in hypotonia-cystinuria syndrome to chromosome 2p16, but later Parvari et al. (2005) corrected and refined the location of the deletion to 2p21. The former title 'homozygous 2p16 deletion syndrome' is retained here for historical purposes.