Phenotypic expansion of Menkes disease in a small cohort: one institution’s experience
Biochemical/Metabolic and Therapeutics
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Introduction
Menkes disease is an X-linked disorder that classically presents in mid-infancy with seizures, failure to thrive, unusual hair, dysautonomia, vascular tortuosity and ectasia, bladder diverticula and hernias. Our cases compare the clinical features of two infants diagnosed with Menkes in rapid chronological succession, one of whom presented prenatally.
Case Presentation
Patient 1: Prenatally, this patient was found to have bilateral congenital pleural effusions, R>L and a thickened nuchal fold without hydrops fetalis at 20 weeks gestation. Fetal echo was normal. He underwent right thoraco-amniotic shunt at 28 5/7 weeks gestation and was also treated with betamethasone. Fluid from the thoraco-amniotic shunt demonstrated lymphocytes, concerning for chylothorax.
At birth, he had diffuse hypotonia, several cephalohematomas, abnormally soft and wrinkled skin and joint contractures of his lower extremities and bilateral clenched hands with ulnar deviation and overlapping fingers. His inpatient workup additionally included temperature instability, hypothyroidism, hyperbilirubinemia, and poor weight gain. Pulmonary effusions had resolved, and his prenatal shunt was autonomously removed.
Patient 2: A 3 mo ex-FT male presented with abnormal movements found to be intractable seizures. He was also noted to have global developmental delay, failure to thrive with history of feeding intolerance, temperature instability, and hypotonia. Physical exam showed a pale infant with soft skin. When his EEG leads were removed, sparse, white, tightly coiled hair and eyebrows were discovered, previously attributed to seborrheic dermatitis.
Diagnostic Workup
Patient 1: Mother’s cfDNA was low-risk male, with a normal male karyotype and SNP microarray from amniocytes. Whole exome sequencing (WES) revealed Menkes disease due to de novo pathogenic variant in ATP7A. Mitochondrial DNA analysis negative.
Patient 2: Biochemical testing had low serum copper and ceruloplasmin, supportive of the suspected diagnosis. WES confirmed a diagnosis of Menkes disease with a maternally inherited ATP7A variant and a low heteroplasmy mitochondrial VUS. An epilepsy panel sent prior to genetics involvement revealed the several nondiagnostic variants also heterozygous in father. Of note, ATP7A was not present in the epilepsy panel.
Treatment and Management
Both families began Copper Histidine treatment shortly after diagnosis (around 1 month of age and 4 months of age, respectively) and continue to participate in the expanded access program. They both tolerate injections well with no site reactions, though patient 1 had to modify his dosing regimen once.
They also both follow a team of specialists for disease management and have revealed additional features, which will be presented in photographs and in a table format highlighting their overlapping phenotypic findings and where they diverge allowing increased knowledge of both untreated and treated Menkes disease.
Discussion
Both cases illustrate the multisystemic phenotypic variability of Menkes syndrome. While there is one other case report of pleural effusions in Menkes, neither prenatal findings nor pulmonary disease are known to be associated with this disease. Additional unusual features include several cephalohematomas, contractures and hypothyroidism. Our first patient’s continued absence of seizures with normal EEG studies further supports the utility of early diagnosis and intervention.
Conclusion
Increasing the natural history knowledge that allows early identification of rare disease continues to be an integral part of genetic care, particularly important as treatment studies are expanding.
Menkes disease is an X-linked disorder that classically presents in mid-infancy with seizures, failure to thrive, unusual hair, dysautonomia, vascular tortuosity and ectasia, bladder diverticula and hernias. Our cases compare the clinical features of two infants diagnosed with Menkes in rapid chronological succession, one of whom presented prenatally.
Case Presentation
Patient 1: Prenatally, this patient was found to have bilateral congenital pleural effusions, R>L and a thickened nuchal fold without hydrops fetalis at 20 weeks gestation. Fetal echo was normal. He underwent right thoraco-amniotic shunt at 28 5/7 weeks gestation and was also treated with betamethasone. Fluid from the thoraco-amniotic shunt demonstrated lymphocytes, concerning for chylothorax.
At birth, he had diffuse hypotonia, several cephalohematomas, abnormally soft and wrinkled skin and joint contractures of his lower extremities and bilateral clenched hands with ulnar deviation and overlapping fingers. His inpatient workup additionally included temperature instability, hypothyroidism, hyperbilirubinemia, and poor weight gain. Pulmonary effusions had resolved, and his prenatal shunt was autonomously removed.
Patient 2: A 3 mo ex-FT male presented with abnormal movements found to be intractable seizures. He was also noted to have global developmental delay, failure to thrive with history of feeding intolerance, temperature instability, and hypotonia. Physical exam showed a pale infant with soft skin. When his EEG leads were removed, sparse, white, tightly coiled hair and eyebrows were discovered, previously attributed to seborrheic dermatitis.
Diagnostic Workup
Patient 1: Mother’s cfDNA was low-risk male, with a normal male karyotype and SNP microarray from amniocytes. Whole exome sequencing (WES) revealed Menkes disease due to de novo pathogenic variant in ATP7A. Mitochondrial DNA analysis negative.
Patient 2: Biochemical testing had low serum copper and ceruloplasmin, supportive of the suspected diagnosis. WES confirmed a diagnosis of Menkes disease with a maternally inherited ATP7A variant and a low heteroplasmy mitochondrial VUS. An epilepsy panel sent prior to genetics involvement revealed the several nondiagnostic variants also heterozygous in father. Of note, ATP7A was not present in the epilepsy panel.
Treatment and Management
Both families began Copper Histidine treatment shortly after diagnosis (around 1 month of age and 4 months of age, respectively) and continue to participate in the expanded access program. They both tolerate injections well with no site reactions, though patient 1 had to modify his dosing regimen once.
They also both follow a team of specialists for disease management and have revealed additional features, which will be presented in photographs and in a table format highlighting their overlapping phenotypic findings and where they diverge allowing increased knowledge of both untreated and treated Menkes disease.
Discussion
Both cases illustrate the multisystemic phenotypic variability of Menkes syndrome. While there is one other case report of pleural effusions in Menkes, neither prenatal findings nor pulmonary disease are known to be associated with this disease. Additional unusual features include several cephalohematomas, contractures and hypothyroidism. Our first patient’s continued absence of seizures with normal EEG studies further supports the utility of early diagnosis and intervention.
Conclusion
Increasing the natural history knowledge that allows early identification of rare disease continues to be an integral part of genetic care, particularly important as treatment studies are expanding.