Predominant Motor Delay as a Major Presenting Clinical Sign in Cutis Laxa— Report of a Case with Review of Literature
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.293457
Source of Support: None, Conflict of Interest: None
Keywords: Autosomal dominant, cutis laxa, motor delay
Cutis laxa is a heterogeneous group of inherited and acquired connective tissue disorders (CTD) characterized by the progressive looseness of skin along with abnormalities of other organs and structures with elastic tissue such as lungs, vasculature, and gastrointestinal tract. The inherited forms of cutis laxa have autosomal dominant, autosomal recessive, or X-linked inheritance. Autosomal dominant cutis laxa (ADCL) is a rare genetically heterogeneous CTD with variable systemic manifestations. Mutation in ELN, FBLN5, and ALDH18A1 genes have been reported in ADCL. Till date, about 50 patients have been reported.,,
Among the patients presenting with mutations in the ALDH181A gene, those with homozygous deletions present with severe cutaneous cutis laxa with cardiovascular manifestations and cataracts. Heterozygous mutations on the other hand present with manifestations like retarded postnatal growth, hypotonia, joint laxity, osteopenia, and osteoporosis. The presentation as a predominantly pure motor delay is challenging in the absence of skin laxity. Here, we report a 2-year-old child who presented with motor delay and joint hyperlaxity.
A 2-year-old male patient presented with chief complaints of gross motor delay. Antenatal and birth history were normal. Birth parameters were normal (birth weight 2.5 kg, length 53 cm, and head circumference not known). Parents noted motor delay by one year of age, and the child was being shown to various practitioners since then.
On presentation to our hospital at two years of age child was noted to have hyperlaxity of joints and hypotonia. The skin was mildly hyperextensible; however, no loose redundant skin folds were seen. Facial features included a broad prominent forehead, small palpebral fissures with deep-set eyes. In addition, he had pes planus and genu recurvatum.
His weight was 9.5 kg (<3rd centile), height 74 cm (<3rd centile), and head circumference 43 cm (<-3 S.D). He attained head holding at eight months of age, sitting without support at one year, and currently stands with support at two years of age. His motor Development Quotient (DQ) was 54. Social and language development was appropriate for age.
His 32-year-old father and 30-year-old mother were healthy adults with no sign of wrinkly skin. His serum calcium was 8.2 u, phosphate 2.8, alkaline phosphatase 265 u, and vitamin D level of 20.3 u at one year of age when he initially presented to the hospital. Over the course of next one year, he had been labeled as nutritional rickets and was given multiple courses of oral and intramuscular vitamin D supplements along with calcium without any improvement.
The patient then presented to the genetic clinic where after evaluation a possibility of cutis laxa was kept in the view of the lax joints and mild hyperextensibility of skin. Appropriate consents were taken for DNA analysis. Genomic DNA was extracted from peripheral leucocytes using standard procedure and clinical exome sequencing was done. Using an Illumina, platform sequence analysis showed a heterozygous c.G1867A mutation in exon 15 of ALDH18A1 gene on chromosome 10. This mutation has not been reported previously in the literature or any control database. This variant is predicted to be deleterious by bioinformatics algorithms such as Scale-Invariant Feature Transform (SIFT), Mutation Taster, Mutation Assessor, protein variation effect analyzer (PROVEAN)_pred, and Phenolyzer.
Mutation in the ALDH18A1 gene is found to be associated with cutis laxa, autosomal dominant 3 (ADCL3) (OMIM#616603). ADCL is a rare disease that can be recognized primarily on the basis of skin findings and aged appearance, however, this feature may appear later.
Despite the presence of hyperlax joints, the clinical phenotype in our patients evoked an initial diagnosis of rickets. The low vitamin D level contributed further to this diagnosis. Despite no improvement with calcium and vitamin supplementation, the delay in diagnosis was about one year, during which he was received multiple courses of Vitamin D and calcium.
ADCL is a genetically heterogeneous condition and shows high clinical variability. The three types of ADCL known are ADCL1(OMIM #123700), ADCL2(OMIM #614434), and ADCL3(OMIM #616603).,, A comparison of the three subtypes is summarized in [Table 1].
To date, about 11 families have been reported with ADCL3 and in seven of the cases, the mutation was de novo, of paternal origin in 2 and had not been tested in others. There was no ethnic prominence. The details of the reported cases have been summarized in [Table 2].
None of them had pulmonary or cardiac complications in contrast to ADCL1 and ADCL2. However, hypotonia and joint laxity were present in all these cases including our case. The present case showed features of hypotonia, brisk deep tendon jerks, lax joints, and broad forehead as reported in previous cases. In addition, he also has pes planus and genu recurvatum. Although he does not have any ocular anomalies or a typical aged appearance at present but requires close follow-up as wrinkling of skin may have a late-onset.
Fisch Zirnasak et al. were the first to report de novo mutation in ALDH18A1 causing ADCL-3 in nine patients, including one case which had been reported in 1991 but with no conclusive molecular diagnosis at that time., A recent case with a de novo heterozygous mutation (p.R138Q) in ALDH18A1 who developed cyclical vomiting has been reported.
Most cases reported in this study have a substitution of arginine at position 138 by glutamine, leucine, or tryptophan. Another de novo mutation was reported by BholaPet al. in 2017, which has a substitution of arginine at position 126 instead of 138 by histidine [Table 2].
Here we report a novel dominant mutation in a patient with ALDH18A1-ADCL. The de novo status, absence of variant in control databases, in silico predicted deleterious effect and the similar clinical features with other reported patients suggest that this could be responsible for the disease. The similar features include growth restriction, microcephaly, motor delay, prominent forehead, hypermobile joints, and hyperextensible skin.
In conclusion, we report the first individual with ALDH18A1-ADCL due to a new mutation with a possibly milder phenotype and highlight the importance of exome sequencing in giving a definite diagnosis. This will also play a role in appropriate genetic counseling. Also, to the treating clinician, we urge to think of alternative causes in children not responsive to Vitamin D in the absence of signs of vitamin D-resistant rickets. Further studies of ALDH18A1 mutation along with genotype-phenotype correlation will, enhance our understanding of the disease and will assist in diagnosis as well as genetic counseling.
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[Table 1], [Table 2]