Endocrine Features of ARCN1 Haploinsufficiency Include Short Stature, Microphallus with Hypospadias (in males), and Hypoglycemia

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Submission ID :
ESPR220
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Abstract: :

Background:  Heterozygous loss-of-function mutations in archain 1 (ARCN1, coat protein I delta subunit) cause a rare disorder that was first described in 2016.  Characteristics include in utero growth restriction (IUGR), Pierre Robin sequence, rhizomelic short stature, and transient glycosylation defects.

 

Objectives:  We describe 3 patients with heterozygous mutations in ARCN1, focusing on the endocrine disorders in these patients.

 

Methods:  Medical records were reviewed. ARCN1 mutations were detected by whole exome sequencing.

 

Results:  Patient 1 is a 5 year old male born at 32 weeks with birth weight 940 g (Z -3.56), Pierre Robin sequence, cleft palate, microphallus, hypospadias, bifid scrotum, elevated liver enzymes, hyperbilirubinemia, transientglycosylation defects, and feeding difficulties. He had fasting ketotic hypoglycemia with plasma glucose 49 mg/dL at 9 hours, betahydroxybutyrate

(BOHB) 2.6 mmol/L, and free fatty acids (FFA) 1.94 mmol/L. Laboratory evaluation for growth was normal. Short stature persisted, so growth hormone (GH, 0.34 mg/kg/week) was started at 27 months with good response (height Z -2.05 to -1.26 in 1 year).

 

Patient 2 is a 3 year old female born full term with birth weight 1984 g (Z -2.88), Pierre Robin sequence, cleft palate, elevated liver enzymes, hyperbilirubinemia, and transient glycosylation defects. Laboratory evaluation for growth was normal. Short stature persisted, so GH (0.3 mg/kg/week) was started at 21 months with good response (height Z -3.02 to -1.64 in 1 year).

 

Patient 3 is an 18 month old male born at 30 weeks with birth weight 770 g (Z -2.93), Pierre Robin sequence, microphallus, hypospadias, bifid scrotum, elevated liver enzymes, hyperbilirubinemia, minor glycosylation changes, and feeding difficulties. Laboratory evaluations for growth and microphallus were normal. He had fasting hyperinsulinism with plasma glucose 44 mg/dL at 5 hours, BOHB 0.3 mmol/L, and FFA 1.66 mmol/L, which transitioned to ketotic hypoglycemia by 14 months of age. He has displayed some catch-up growth, but current height Z is -2.34.

 

Conclusions:  These patients are similar to the 5 published cases with heterozygous ARCN1 mutations. Although not previously highlighted, microphallus with hypospadias is common in males with this disorder. This is the first description of hypoglycemia and GH therapy in patients with ARCN1 mutations. We recommend that ARCN1 haploinsufficiency be considered in patients with Pierre Robin sequence, IUGR, elevated liver enzymes, hyperbilirubinemia, and/or microphallus. The presentation is similar to congenital disorder of glycosylation type It (PGM1-CDG), but only transient or minor glycosylation changes are detected when they are ill. Providers should evaluate for hypoglycemia and consider growth hormone therapy for insufficient catch-up growth.

The Children's Hospital of Philadelphia
Children's Hospital of Philadelphia
Human Genetics, Children's Hospital of Philadelphia
Human Genetics, Children's Hospital of Philadelphia
Pathology & Lab Medicine, Children's Hospital of Philadelphia, Philadelphia

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