Clinical characteristics.

IDEDNIK syndrome is characterized by enteropathy, poor weight gain, growth deficiency, skin manifestations (ichthyosis, erythroderma, and keratoderma), sparse hair, global developmental delay, mild-to-severe intellectual disability, and deafness. Additional manifestations can include liver disease, recurrent infections, and hematologic and ocular manifestations (photophobia, corneal scarring, and keratitis). Reduced serum ceruloplasmin and total copper levels are common. Some individuals have findings on brain MRI (cerebral atrophy, basal ganglia abnormalities, and thin corpus callosum). Death prior to age two years occurs in some individuals due to severe enteropathy or sepsis; in others survival into adulthood is reported.

Diagnosis/testing.

The diagnosis of IDEDNIK syndrome is established in a proband by identification of biallelic pathogenic variants in AP1B1 or AP1S1 by molecular genetic testing.

Management.

Targeted therapy: Treatment with oral zinc acetate therapy to reduce liver copper overload has been reported to improve behavioral disturbances, skin manifestations, and cognitive function in some individuals. Zinc sulfate may be an alternative, less expensive treatment option. Experience is limited with this targeted therapy.

Supportive care: Dietary modification and potential parenteral supplementation for enteropathy; feeding therapy; gastrostomy tube placement as needed; treatment options for skin manifestations include low-dose oral acitretin, skin emollients and topical lactic acid, frequent emollient application and short courses of topical cortical steroids or pimecrolimus ointment, and 50% urea ointments; developmental and educational support; hearing aids as needed for sensorineural hearing loss; community hearing services; standard treatment of seizures and peripheral neuropathy by an experienced neurologist; supportive treatment as needed for liver disease; standard treatment for recurrent infections; supportive treatment as needed for hematologic manifestations, and occasionally transfusion may be necessary; standard treatment of cataracts and other ocular manifestations per ophthalmologist; treatment of cryptorchidism per urologist; treatment of hypothyroidism and growth hormone deficiency per perinatologist; social work and family support.

Surveillance: At each visit, assess growth parameters, nutritional status, safety of oral intake, diarrhea, skin and hair manifestations, developmental progress and educational needs, mobility and self-help needs, seizures and peripheral neuropathy, behavioral issues, liver function tests, complete blood count, evidence of aspiration and respiratory infections, and family needs. Audiology evaluation as recommended by audiologist; ophthalmology evaluation for keratitis, cataract, and accommodative esotropia as recommended by ophthalmologist; assess thyroid function and for growth hormone deficiency as recommended by endocrinologist.

Evaluation of relatives at risk: Clarify the genetic status of apparently asymptomatic older and younger at-risk sibs in order to identify as early as possible those who would benefit from prompt initiation of zinc acetate treatment.

Genetic counseling.

IDEDNIK syndrome is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an AP1B1 or AP1S1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the AP1B1 or AP1S1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

IDEDNIK syndrome should be suspected in probands with the following clinical, laboratory, histopathology, and imaging findings and family history.

Clinical findings

• Infantile-onset diarrhea
• Poor weight gain and growth deficiency
• Skin and hair manifestations: ichthyosis, erythroderma, hyperkeratosis, sparse hair, and alopecia
• Global developmental delay
• Hypotonia
• Sensorineural hearing loss
• Intellectual disability (mild to severe)
• Hepatomegaly
• Recurrent infections
• Ocular manifestations: photophobia, corneal scarring, and keratitis
• Characteristic facial features: high anterior hairline, frontal bossing, low-set ears, and depressed nasal bridge

Laboratory findings

• Reduced ceruloplasmin and total serum copper levels
• Increased serum free copper level
• Elevated transaminases
• Elevated plasma total bile acid levels
• Elevated very long-chain fatty acids
• Anemia and/or thrombocytopenia
• Increased urinary copper excretion (2 individuals)

Histopathology

• Duodenal biopsy: mild villous blunting
• Liver biopsy: increased copper content (1 individual), liver fibrosis (3 individuals), cirrhosis (2 individuals)

Imaging findings on brain MRI

• Cerebral atrophy (8 of 11 individuals)
• Basal ganglia abnormalities (3 of 9 individuals)
• Thin corpus callosum (3 of 5 individuals)

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history or consanguinity does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of IDEDNIK syndrome is established in a proband by identification of biallelic pathogenic (or likely pathogenic) variants in AP1B1 or AP1S1 by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic AP1B1 or AP1S1 variants of uncertain significance (or of one known pathogenic variant and one variant of uncertain significance in the same gene) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (concurrent gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

IDEDNIK syndrome is characterized by enteropathy, growth deficiency, skin manifestations (ichthyosis, erythroderma, and keratoderma), sparse hair, global developmental delay, mild-to-severe intellectual disability, and deafness. Additional manifestations can include liver disease, recurrent infections, and hematologic and ocular manifestations. To date, 24 individuals have been diagnosed with IDEDNIK syndrome – ten individuals with AP1B1-related IDEDNIK syndrome [Alsaif et al 2019, Boyden et al 2019, Ito et al 2021, Meriç et al 2021, Vornweg et al 2021, Faghihi et al 2022, Vasconcelos et al 2023] and 14 individuals with AP1S1-related IDEDNIK syndrome [Saba et al 2005, Montpetit et al 2008, Martinelli et al 2013, Incecik et al 2018, Klee et al 2020, Lu et al 2023]. The following description of the phenotypic features associated with this condition is based on these reports.

Enteropathy. Severe, persistent diarrhea typically begins in early infancy, resulting in significant nutritional deficiencies and poor weight gain. Diarrhea is often persistent. Individuals with AP1S1-related IDEDNIK syndrome exhibit a more severe form of diarrhea that has resulted in death within the first few months of life in some infants.

Growth deficiency. Birth weight can vary from between two to three standard deviations (SD) below the mean to normal. Poor weight gain is common and weight in older children ranges from one to five SD below the mean. One infant with a birth weight of 2,660 grams had significant weight loss by age two months [Klee et al 2020]. Body mass index in some individuals is more than three SD below the mean [Alsaif et al 2019, Vasconcelos et al 2023].

Birth length can also vary from normal to three SD below the mean. Growth deficiency varies but can be progressive, with a height range of 2-3 SD below the mean to 4.7 SD below the mean (reported in 1 child, age 3 years) [Alsaif et al 2019]. In one child, growth delay was partially attributed to deficient pancreatic enzyme production, which spontaneously recovered in childhood [Boyden et al 2019]. Severe short stature with growth hormone deficiency and hypothyroidism was noted in one individual [Meriç et al 2021].

Head circumference is often normal at birth. Head circumference reported in children with IDEDNIK syndrome varies from one to two SD below the mean [Faghihi et al 2022], and progressive microcephaly (decreasing from normal to 2 SD below the mean) has been reported in one child, age seven years [Martinelli et al 2013, Alsaif et al 2019].

Skin manifestations include ichthyosis, erythroderma, and hyperkeratosis. Skin involvement becomes apparent at or shortly after birth. Ichthyosis, a defining feature of IDEDNIK syndrome, is characterized by dry, scaly skin. The severity of ichthyosis can vary widely among individuals. It can affect the entire body or be more pronounced in the extremities. Erythroderma and hyperkeratosis are present in infancy and early childhood. The severity ranges from mild, with diffuse thin, white scaling and pink erythroderma, to more severe forms, including exfoliative erythroderma that progressively worsens, often accompanied by severe pruritus. Ichthyosiform erythroderma, generalized scaling, erythematous plaques, and migrating patches have all been reported. Hyperkeratosis can also be moderate to pronounced, affecting specific areas (e.g., scalp, palmar and plantar surfaces), to nearly the entire body and sometimes accompanied by papules.

Hair manifestations. The majority of affected individuals exhibit sparse scalp hair, while four individuals presented with partial alopecia. Alopecia has been described as patchy with thick, yellow, plate-like scales on the scalp. Some affected individuals were described as having slow-growing scalp hair with normal texture, while others had wiry, woolly, or brittle hair. Some individuals had grayish hair color. One individual had trichorrhexis nodosa, confirmed with light microscopy [Martinelli et al 2013]. However, direct and polarizing light microscopy were normal in another affected individual.

Global developmental delay. Hypotonia causing motor delay is a frequently reported feature (8/8 reported individuals), and four individuals had more pronounced hypotonia in the lower limbs [Saba et al 2005]. In early childhood, affected individuals show mild-to-moderate global developmental delay, ranging from absent head control at age five months in one individual to delayed onset of sitting and walking. Most affected individuals respond well to physical therapy, and by late childhood these individuals have normal motor development.

Speech development is also frequently delayed. Of note, factors such as sensorineural hearing loss contribute to speech delay as well as specific delays in nonverbal communication [Faghihi et al 2022].

Sensorineural hearing loss. Eighteen of 18 reported individuals have sensorineural hearing loss, with variability in severity. While some affected individuals exhibit hearing impairment from infancy, others experience a gradual progression to profound hearing loss. One individual had mild unilateral hearing loss at age eight months [Lu et al 2023]. One individual was noted to have partial hearing loss as an infant and developed profound hearing loss after an episode of meningitis at age three years [Boyden et al 2019].

Intellectual disability. The severity of intellectual disability varies markedly, ranging from mild to severe. Individuals with AP1B1-related IDEDNIK syndrome typically exhibit normal cognitive function to moderate intellectual disability. Conversely, most affected individuals with AP1S1-related IDEDNIK syndrome tend to have severe intellectual disability.

Seizures. Three individuals were noted to exhibit seizures; one had febrile seizures with onset at age 2.5 years, controlled with an anti-seizure medication [Meriç et al 2021]. Another individual had an episode of myoclonic seizures on postnatal day eight that responded to phenobarbital [Klee et al 2020]. Phenobarbital was also effective in managing seizures in the third individual at 11 days of life [Lu et al 2023].

Peripheral neuropathy. All three reported adults (ages: 19 years, 27 years, and 28 years) with AP1S1-related IDEDNIK syndrome presented with peripheral neuropathy; the age of onset of neuropathy was not reported. To date, no affected individuals with AP1B1-related IDEDNIK syndrome have been reported to have peripheral neuropathy; this might be due to the young age of most reported individuals with AP1B1-related IDEDNIK syndrome, suggesting that the development of peripheral neuropathy could be age dependent [Martinelli et al 2013, Alsaif et al 2019]. Although peripheral neuropathy has not been identified in the only known adult with AP1B1-related IDEDNIK syndrome, last evaluated at age 33 years, nerve conduction studies have not been done [Boyden et al 2019].

Neurobehavioral/psychiatric manifestations. One individual with severe intellectual disability showed features of autism spectrum disorder at age seven years, including deficits in social interaction and communication, repetitive behaviors, and inflexible adherence to routines [Martinelli et al 2013].

Liver manifestations. Liver involvement in IDEDNIK syndrome manifests variably as hepatopathy, elevated transaminases, elevated plasma total bile acid levels, and/or hepatomegaly. Twelve individuals were reported to have hepatopathy, and elevated liver transaminases were reported in twelve individuals. Cholestasis and elevated plasma total bile acid levels were reported in five individuals, with two individuals reported to have icterus. Three individuals had hepatomegaly. Liver fibrosis was reported in three individuals, and cirrhosis in two individuals. Liver biopsy was obtained from two individuals, and only one of these showed liver copper accumulation.

Recurrent infections. Nine individuals with IDEDNIK syndrome experienced recurrent infections, typically respiratory in nature, and one individual died of septic shock [Klee et al 2020].

Hematologic manifestations. Mild-to-moderate anemia has been reported in three individuals. Low serum ferritin was also present in one individual with mild anemia [Vasconcelos et al 2023]. Anemia without acute bleeding in one individual required transfusion therapy [Klee et al 2020].

Thrombocytopenia was reported in four individuals. One individual had platelet counts with range 223-843 K/µL [Lu et al 2023]. One individual had mild episodic thrombocytopenia throughout her life; another individual with persistent moderate thrombocytopenia had dysmegakaryopoiesis identified on bone marrow biopsy [Boyden et al 2019]. There are no reports of individuals developing myelodysplastic syndrome or acute myelogenous leukemia.

Intermittent peripheral eosinophilia was reported in one individual (range 0.15-1.21 K/µL) [Lu et al 2023].

Ocular manifestations. While the ocular phenotype varies among individuals, photophobia is notably the most common feature, affecting six individuals. Additional ocular manifestations include bilateral ectropion (3 individuals), corneal scarring (3 individuals), keratitis (2 individuals), cataracts (2 individuals), high myopia (1 individual), and hyperopic astigmatism with accommodative esotropia (1 individual).

Characteristic facial features. High anterior hairline and low-set ears were described in seven individuals. Depressed nasal bridge was described in six individuals, and frontal bossing was described in two individuals.

Other

• Hypoplastic scrotum with cryptorchidism (1 individual)
• Testicular atrophy (1 individual)
• Primary hypothyroidism and growth hormone deficiency (1 individual)
• Dilated cardiomyopathy identified on echocardiogram resolved in the first year of life (1 individual)
• Recurrent venous thromboses (1 individual)
• Severe osteoporosis (1 individual)
• Prominent abdomen (2 individuals)

Prognosis. Death in early childhood (prior to age two years) has been reported in eight individuals with AP1S1-related IDEDNIK syndrome due to severe enteropathy or sepsis. Survival into adulthood is possible; one reported individual with AP1S1-related IDEDNIK syndrome is alive at age 28 years. Early demise in infancy is not common in those with AP1B1-related IDEDNIK syndrome.

Phenotype Correlations by Gene

Individuals with AP1B1-related IDEDNIK syndrome typically exhibit normal intellect to moderate intellectual disability. Conversely, most affected individuals with AP1S1-related IDEDNIK syndrome have severe intellectual disability.

Individuals with AP1S1-related IDEDNIK syndrome are more likely to have cerebral atrophy and hepatopathy; severe infantile-onset diarrhea is also more common, resulting in death within the first few months of life in some infants. Peripheral neuropathy has only been reported in individuals with AP1S1-related IDEDNIK syndrome.

Nomenclature

IDEDNIK syndrome was initially referred to as erythrokeratodermia variabilis type 3 (EKV3) [Saba et al 2005]. The disorder was renamed MEDNIK syndrome (mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma) [Montpetit et al 2008] and later IDEDNIK syndrome (reflecting an emphasis on intellectual disability rather than mental retardation) [Lu et al 2023].

The AP1B1-related phenotype was initially described as MEDNIK-like syndrome [Alsaif et al 2019, Ito et al 2021] and is categorized in OMIM (242150) as KIDAR syndrome (keratitis-ichthyosis-deafness, autosomal recessive) [Vornweg et al 2021, Faghihi et al 2022, Vasconcelos et al 2023]. The authors observe that IDEDNIK syndrome is a more accurate and clinically useful categorization because (1) the AP1B1-related phenotype aligns most closely with the features encompassed by the IDEDNIK acronym and (2) keratitis may not be a defining feature of the syndrome (thus challenging the suitability of the KIDAR nomenclature).

Prevalence

IDEDNIK syndrome is rare, with only 24 affected individuals reported to date.

A founder variant (c.183-2A>G) has been described in the French Canadian population from Quebec [Saba et al 2005, Montpetit et al 2008]. To date, eight individuals from this population have been identified with IDEDNIK syndrome; carrier frequency in this population has not been reported.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with IDEDNIK syndrome, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

IDEDNIK syndrome presents a unique combination of clinical and biochemical signs that overlap Menkes disease and Wilson disease. Treatment with zinc acetate, a drug shown to reduce intestinal copper absorption in Wilson disease, has been found to significantly improve clinical manifestations in individuals with IDEDNIK syndrome, including reducing liver copper and plasma total bile acid levels and improving behavioral disturbances, cognitive function, and itching. This finding suggests a new approach to treating individuals with IDEDNIK syndrome as a copper metabolism defect [Bruha et al 2011, Martinelli et al 2013].

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Evaluation of Relatives at Risk

Although it is expected that sibs of a proband who have inherited biallelic AP1B1 or AP1S1 pathogenic variants would have signs of IDEDNIK syndrome in infancy, it is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs in order to identify as early as possible those who would benefit from prompt initiation of zinc acetate treatment.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

IDEDNIK syndrome is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for an AP1B1 or AP1S1 pathogenic variant.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an AP1B1 or AP1S1 pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for an AP1B1 or AP1S1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. To date, individuals with IDEDNIK syndrome are not known to reproduce.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an AP1B1 or AP1S1 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the AP1B1 or AP1S1 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk sibs for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of individuals known to have an AP1B1 or AP1S1 pathogenic variant, particularly if consanguinity is likely. An AP1S1 founder variant has been identified in French Canadian families in Quebec (see Table 7).

Prenatal Testing and Preimplantation Genetic Testing

Once the AP1B1 or AP1S1 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

AP1B1 and AP1S1 encode the large beta subunit and small sigma subunit, respectively, of the adaptor protein complex 1 (AP-1). This complex mediates trafficking between the trans-Golgi network, endosomes, and the plasma membrane. Pathogenic variants in AP1B1 or AP1S1 result in the defective functioning of the AP-1 complex, crucial for proper intracellular trafficking of copper transporters (encoded by ATP7A and ATP7B), leading to abnormal copper metabolism and a unique clinical and biochemical phenotype combining features of Menkes disease and Wilson disease [Martinelli et al 2013, Alsaif et al 2019].

Mechanism of disease causation. Loss of function

AP1B1-specific laboratory technical considerations. AP1B1 has homologous upstream and downstream regions that can complicate PCR amplification and sequence analysis. Specific primers and in silico PCR may be required [Alsaif et al 2019].

Author Notes

Dr Fowzan Alkuraya (as.ude.crhsfk@ayaruklaf) is actively involved in clinical research regarding individuals with IDEDNIK syndrome. Dr Alkuraya would be happy to communicate with persons who have any questions regarding diagnosis of IDEDNIK syndrome or other considerations. Dr Alkuraya is also interested in hearing from clinicians treating families affected by IDEDNIK syndrome in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.

Acknowledgments

Our heartfelt thanks to the participating affected individuals and their families. Your invaluable contribution has been the cornerstone of a better understanding of IDEDNIK syndrome.

Revision History

• 14 November 2024 (sw) Review posted live
• 2 April 2024 (ha) Original submission

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