Chromosome Xp22.3 deletion syndrome with X-linked ichthyosis, Kallmann syndrome, short stature, generalized epilepsy, hearing loss, attention deficit hyperactivity disorder, and intellectual disability – A rare report with review of literature

INTRODUCTION

Chromosome Xp22.3 deletion syndrome is a very rare contiguous gene deletion syndrome with variable phenotype, depending on the large terminal or interstitial codeletions of adjacent genes that are physically clustered. This contiguous gene syndrome is due to the deletion of genes from the distal short arm of the X chromosome (Xp), including the short-stature homeobox (SHOX), anosmin-1 (ANOS1), arylsulfatase (ARSL), neuroligin-4 (NLGN4), and steroid sulfatase (STS) genes.^[1] This syndrome is characterized by X-linked ichthyosis (XLI), Kallmann syndrome (KS), short stature, generalized epilepsy, neurodevelopmental disorders including autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and intellectual disability (ID), sensorineural hearing loss, strabismus, and bony deformities including chondrodysplasia punctata (CDP), obesity, and ocular albinism.^[1-3] The other dysmorphism features reported are frontal bossing, hypertelorism, depressed nasal bridge, high-arched palate, retrognathia, and flat occiput.^[4,5] Based on the deletion lengths, the clinical phenotypes occur independently from each other or in various combinations as a contiguous gene syndrome.^[6] Only about 34 cases have been reported in the literature. Here, we report a case of Xp22.3 deletion syndrome (8.1 Mb contiguous deletion), including ANOS1, ARSL, NLGN4X, SHOX, and STS genes, along with a review of available literature [Table 1].

CASE PRESENTATION

A 10-year-old boy presented with global developmental delay, decreased hearing since birth, and hyperactivity. He also had a history of generalized tonic-clonic seizures since five years of age, with 1–2 episodes/year. He was first born to third-degree consanguineously married parents. The antenatal and perinatal periods were unremarkable. There was no significant family history. On examination, he had a height of 116 cm (−3.5Z, stunting), a weight of 25.2 Kg (−1.3Z), body mass index of 18.7 kg/m², and a head circumference of 53 cm. The upper-to-lower segment ratio (US: LS) was 0.93. The mid-parental height was 159 cm. He had coarse facies with thick arched eyebrows, long philtrum, retrognathia, depressed nasal bridge, high arched palate, brachytelephalangy, brachymetatarsia, and mild scoliosis [Figure 1a-c]. He had dry, scaly skin lesions over the axilla, lateral side of the chest, and abdomen, suggestive of ichthyosis [Figure 1d-f]. On genitalia examination, he had a stretched penile length of 3.5 cm and a testicular volume of <2cc (Tanner staging – G1, no axillary and pubic hair). The rest of the systemic examination was normal, with no organomegaly. Fundus examination was normal. Based on the clinical presentation, the possibilities of multiple sulfatase deficiency and Sjogren–Larsson syndrome were considered.

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Figure 1:

Clinical features in the Index Child. (a-f) shows dysmorphic features and Ichthyosis. (d) shows pectus excavatum. (a) Facial dysmorphism, (b) brachytelephalangy, (c) high-arched palate, (d) ichthyosis over the abdomen, (e) ichthyosis over the axilla, (f) ichthyosis over the back.

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He had a normal hemogram, renal, liver, and thyroid function tests, and a normal bone metabolic profile. He had normal cortisol levels (9.92 [3.09–16.66] μg/dL), low levels of testosterone (7.0 [241–827] ng/dL), luteinizing hormone (0.21 [2.8–6.8] mIU/mL), prolactin (50.4 [87– 392] mIU/L), and insulin growth factor 1 (9.05 [131– 490] ng/mL). The testing for smell with common odors revealed anosmia in the index child. The urinary testing for mucopolysaccharides was negative. Ultrasonogram study of the abdomen and pelvis was normal. The 2D echocardiography study was normal. The skeletal survey revealed abnormal development of distal phalanges of bilateral 1^st – 4^th fingers, coxa valga, and mild concavity with enlarged intervertebral discs in the lower thoracic and lumbar regions. Magnetic resonance imaging showed a normal pituitary gland, crowded posterior fossa with effacement of the fourth ventricle, and cerebellar tonsillar ectopia. Brain-evoked auditory response testing revealed bilateral moderate (60 dB) hearing loss. Clinical exome sequencing revealed a contiguous deletion of size (~8.10 Mb), spanning genomic location chrX:g.(_630898)_ (8732037_)del encompassing multiple genes including ANOS1, ARSL, NLGN4X, SHOX, STS was detected, suggestive of chromosome Xp22.3 deletion syndrome. The child is currently on a multidisciplinary follow-up.

LITERATURE SEARCH

A literature review was performed from the year 2023 to the oldest available report in English on Chromosome Xp22.3 deletion syndrome from the PubMed/MEDLINE, Google Scholar, and SCOPUS databases. All articles describing Chromosome Xp22.3 deletion syndrome were identified, and duplicates were removed. A total of 34 cases (excluding the index child) have been described in the literature and are summarized in Table 2.

DISCUSSION

The genetic analysis of the index child revealed a contiguous deletion of size (~8.10 Mb) in terminal Xp22.3 region encompassing multiple genes, including ANOS1 (KAL1), ARSL, NLGN4X, SHOX and STS, suggestive of chromosome Xp22.3 deletion syndrome [Figure 2]. This deletion was classified as a “likely pathogenic” copy number variation based on the American College of Medical Genetics guidelines.^[7] The index child’s distinctive features were ichthyosis, global developmental delay, short stature, bilateral hearing loss, and hyperactivity. In the index child, along with signs of hypogonadism and anosmia, KS was diagnosed.

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Figure 2:

Chromosome Xp22.3 region with associated significant Genes. G-banding Ideogram of X chromosome (800 bphs resolution) showing Xp22.3 region with the Genes of Interest.

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The deletions of the Xp22.31 – p22.33 region result in contiguous gene syndromes with various phenotypical combinations of XLI, KS, short stature, CDP, developmental delay, ASD, ID, strabismus, obesity, ocular albinism, and bilateral hearing loss [Table 1].^[1,8-10] The XLI (MIM#308100) is characterized by dry, dark-colored scales over the trunk and limbs, which is due to deletions of STS gene.^[11] The absence of STS causes the accumulation of cholesterol sulfate in the stratum corneum, resulting in impaired skin permeability and hyperkeratosis.^[12] The ANOS1 gene is located near the STS gene near the Xp22.3 locus, and the deletion of the ANOS1 gene causes X-linked KS. The ANOS1 gene encodes the anosmin-1 protein, which is present in the cerebral cortex and olfactory system. Ansomin-1 also mediates the adhesion and the axonal migration of gonadotrophin-releasing hormone (GnRH) neurons.^[10] KS (MIM#308700) is due to deficiency of GnRH and hypoplasia of olfactory bulbs and is characterized by hypogonadotropic hypogonadism, anosmia/hyposmia, and other features may include cleft lip/palate, hearing loss, and unilateral renal agenesis.^[10]

SHOX on the Xp gene is a homeobox gene involved in skeletal development and maturation. SHOX-related disorders have a highly variable phenotypic spectrum ranging from short stature to Leri-Weill dyschondrosteosis, which consists of a triad of mesomelia, short stature, and Madelung deformity (MD) (MIM#300582).^[13] ARSL gene encodes ARSL, a member of the sulfatase family that is essential for the composition of bone and cartilage matrix.^[14] The deletion of these genes results in short stature and X-linked chondrodysplasia punctata-1 (CDPX1). CDPX1 (MIM#302950) is characterized by brachytelephalangy – short distal phalanges, CDP – stippled epiphyses, nasomaxillary hypoplasia, short stature, hearing loss, vertebral abnormalities including dysplastic and hypoplastic vertebrae, developmental delay, ID, and cataracts.^[14]

NLGN4X gene encodes the cell surface proteins of neurons. They are involved in forming and remodeling the synapses in the central nervous system. The deletion of NLGN4X causes X-linked ASD (MIM#300495) and X-linked ID (MIM#300495).^[15-19] The deletion of other genes, including variably charged protein X-A (VCX-A), can also result in X-linked ID. The deletions of NLGN4X and VCX-A can cause variable phenotypes, including normal intellect.^[5,15-17] Recently, in these associated contiguous gene syndromes involving Xp22.3, ADHD has been reported.^[1,9,18,19]

In Xp22.3 microdeletions, cortical heterotopias, hypoplasia of corpus callosum, mild enlargement of sella turcica, olfactory bulb dysplasia (KS patients), and Dandy–Walker malformation have been reported.^[4,8,10] Similarly, cerebellar tonsillar ectopia was noted in the index child, which has not been reported in the literature. The available literature on contiguous Xp22.3 deletion was reviewed and summarized in Table 2.

CONCLUSION

Contiguous gene syndromes exhibit complex disease phenotypes stemming from the microdeletion of multiple adjacent contiguous genes. These phenotypical associations serve as valuable indicators for the diagnosis, underscoring the critical role of recognizing them in establishing diagnoses and multimodal management planning for these patients.