Trichorrhexis nodosa: An important clue in the diagnosis of citrullinaemia type I

INTRODUCTION

Citrullinaemia type I (CTLN1: OMIM#215700) also known as arginosuccinate synthetase (ASS) deficiency is an autosomal recessive urea cycle disorder caused by mutations in the ASS1 gene, leading to impaired synthesis of argininosuccinate from citrulline and aspartate.^[1]

The phenotypic manifestations can vary based on several factors, especially enzyme levels and can be broadly categorised into the classic or neonatal presentation: Where the child manifests with features of hyperammonaemia such as vomiting, lethargy, tone abnormalities, encephalopathy and features of raised intracranial pressure, while the non-classic form manifests in a later period with mild neurological manifestations including headache mimicking migraine, visual disturbances, balance issues, mild cognitive abnormality and intermittent/fluctuating consciousness, with some cases having only symptoms during pregnancy and postpartum.^[1-3] Dermatological signs such as trichorrhexis nodosa, though rare, may provide vital diagnostic clues in the diagnosis of urea cycle disorders such as argininosuccinate lyase deficiency and citrullinaemia.^[4] Early recognition and diagnosis of the disorder help in early intervention with protein restriction, arginine supplementation and liver transplant, which can help prevent morbidity and mortality with good outcomes. Here, we present one such case, where hair abnormality was an essential clue in the diagnosis, and highlight the same.

CASE REPORT

A 2-year-old boy, born to a non-consanguineous couple with a history of recurrent spontaneous abortions, presented with global developmental delay and recent neuroregression. The child had irritability, excessive crying and episodic lethargy. Hair looks woolly and lusterless as shown in Figure 1. Neurological examination revealed quadriparesis with spasticity and brisk deep tendon reflexes.

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Figure 1:

(a and b) Clinical photographs of the child show that hair was woolly and lusterless.

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Investigations revealed a serum ammonia level of 245 µg/dL, elevated lactate (18 mg/dL) and mixed respiratory alkalosis with metabolic acidosis on arterial blood gas analysis. Hair was mounted on a glass slide and examined for hair shaft abnormalities under light microscopy. Hair shaft examination showed trichorrhexis nodosa [Figure 2], which further provided us with a strong clue for the underlying genetic disorder and citrullinaemia. Magnetic resonance imaging scans demonstrated bilateral symmetrical T2/fluid-attenuated inversion recovery hyperintensities in the periventricular white matter, as depicted in Figure 3. Tandem mass spectrometry results showed markedly elevated citrulline levels (1099.21 µmol/L; normal range: 10–40 µmol/L). Genetic testing identified a known pathogenic homozygous missense variant c.910C>T, p.(Arg304Trp) in the ASS1 gene. The child was treated with a protein-restricted diet, sodium benzoate, carnitine, arginine supplementation and citrulline-free metabolic formula. Significant clinical improvement was observed, and no recurrence of encephalopathy was observed during the 3-year follow-up.

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Figure 2:

(a and b) Hair shaft examination under a microscope revealed trichorrhexis nodosa.

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Figure 3:

(a and b) Magnetic resonance imaging brain – bilateral T2/fluid-attenuated inversion recovery hyperintense signal changes in periventricular frontal and posterior with diffuse patchy hyperintensities in white matter.

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DISCUSSION

CTLN1 classically presents with hyperammonaemia encephalopathy in neonates. However, atypical presentations beyond infancy often pose diagnostic challenges. In this case, developmental regression, spasticity and encephalopathy pointed towards a metabolic aetiology.^[1]

Trichorrhexis nodosa, characterised by hair shaft thickening and nodular fractures, is commonly reported in argininosuccinic aciduria but is rarely documented in CTLN1. The other inherited causes of the hair abnormality include biotinidase deficiency, Menkes kinky hair disease, tricho-hepato-enteric syndrome, Goltz syndrome, Netherton syndrome, Noonan’s wooly hair syndrome and trichothiodystrophy, hypothyroidism, nutritional deficiencies and physical and chemical trauma are the major causes of acquired trichorrhexis nodosa.^[4] The underlying mechanism in inherited disorders is likely to involve impaired amino acid content affecting hair structure.^[5]

Recognition of this subtle clinical clue facilitated a timely metabolic workup and targeted treatment. Genetic confirmation helped counsel the family regarding the risks of recurrence and prenatal diagnosis.

CONCLUSION

This case underscores the importance of maintaining a high index of suspicion for inborn errors of metabolism in children presenting with regression and encephalopathy. Hair examination can offer an accessible and cost-effective diagnostic clue. Trichorrhexis nodosa, although rare, may serve as a valuable marker for underlying urea cycle disorders, such as CTLN1.