**5. Syndromes associated with cystinuria**

There are three recessive contiguous gene syndromes associated with cystinuria. These are the hypotonia-cystinuria syndrome (HCS) [12], atypical hypotonia-cystinuria syndrome [13] and 2p21 deletion syndrome [4]. Each of these syndromes includes the homozygous disruption of the *SLC3A1* gene, and therefore produce cystinuria type AA as part of their clinical phenotype.

Hypotonia-cystinuria syndrome arises from homozygous deletion of two genes, *SLC3A1* and *PREPL*, and has the least severe phenotype. The main phenotypical features are infantile hypotonia, poor sucking and associated feeding problems, growth hormone deficiency leading to growth restriction, mild facial dysmorphic features and cystinuria type AA [12]. Atypical hypotonia-cystinuria syndrome, which features disruption to three contiguous genes, *SLC3A1*, *PREPL* and *C2orf34*, produces an intermediate phenotype featuring mild to moderate intellectual disability in addition to the features of hypotonia-cystinuria syndrome [13]. The 2p21 deletion syndrome, resulting from homozygous loss of four contiguous genes, *SLC3A1*, *PREPL*, *C2orf34* and *PPM1B*, produces a more severe phenotype, as expected, owing to the higher number of genes affected [4]. Patients with 2p21 deletion syndrome may have neonatal seizures, severe developmental delay and lactic acidosis in addition to the typical features associated with hypotonia-cystinuria syndrome (**Table 1**).
