Abstract
IMAGe syndrome (Intrauterine growth restriction (IUGR), Metaphyseal dysplasia, Adrenal hypoplasia congenita, and Genital anomalies) is a rare, multisystem disorder caused by mutations in the PCNA-binding domain of CDKN1C. Reported here is a male infant diagnosed with IMAGe syndrome by CDKN1C sequencing at 3 months of age. He presented with IUGR, primary adrenal insufficiency with adrenal crisis in the neonatal period, dysmorphic facies, and bilateral cryptorchidism. Interestingly, he demonstrates several additional clinical findings not previously reported with IMAGe syndrome including congenital hypothyroidism, recurrent bacterial infections, and severe eczema.
Introduction
I ntrauterine growth restriction, Metaphyseal dysplasia, Adrenal hypoplasia congenita, and Genital anomalies (IMAGe) was first officially reported by Vilain et al. [8]. There has been a total of 11 articles describing 21 patients [1, 3–8]. All shared intrauterine growth restriction (IUGR), facial dysmorphisms, and adrenal insufficiency [1–3, 5–8]. Adrenal crisis ensues within a few days of life in the majority of patients. Genital anomalies have been present in all diagnosed males [3–6, 8]. The majority of patients have documented epiphyseal and/or metaphyseal dysplasia with delayed bone age being a common finding [1].
The association has recently been termed a syndrome after identification of causative mutations in the proliferating cell nuclear antigen (PCNA)-binding domain of the cyclin-dependent kinase inhibitor 1C (CDKN1C) gene located on chromosome 11p15.5 [2]. CDKN1C encodes a protein vital in inhibiting cell cycle progression and is located within a cluster of genes that regulate growth and development [2]. Interestingly, methylation abnormalities leading to loss-of-function in CDKN1C may cause Beckwith-Wiedemann (BW) syndrome (an overgrowth disorder). In contrast, missense mutations localized to a highly conserved region of the PCNA-binding domain of CDKN1C result in a gain-of-function with excess inhibition of growth and differentiation [2]. CDKN1C expression has been verified to be abundant in developing adrenal tissue, promoting the adrenal hyperplasia in BW syndrome and adrenal hypoplasia in IMAGe syndrome [2]. Owing to imprinting, only maternal transmission results in IMAGe syndrome [2].
Clinical report
This patient is a male infant delivered at a referring institution at 34 6/7 weeks’ gestation to a 32-year-old G6P3023 mother. The parents were unrelated, and the mother’s previous children have no known genetic abnormalities. She was followed prenatally for IUGR, short long bones, and increased nuchal translucency. The infant was asymmetrically small for gestational age, with a birth weight of 1710 g (3%), length of 39 cm (<<3%), and head circumference of 33.5 cm (90%). Physical exam noted skin hyperpigmentation, prominent/broad forehead, small jaw, low-set ears, short extremities, and no palpable testes. Positive-pressure ventilation (PPV) was required from birth. Echocardiograms demonstrated persistent pulmonary hypertension of the newborn. He was transferred from hospital of birth on day of life (DOL) 12 due to concern for left lower extremity arterial thrombus. At the time of transfer, he was intubated and mechanically ventilated.
In our institution, hypercoagulability work-up was negative, and there were no further concerns for clot formation. The patient displayed significant respiratory distress requiring PPV (mechanical ventilator or nasal continuous positive airway pressure). He eventually required a tracheostomy for traumatic subglottic stenosis. Pulmonary hypertension persisted. Hypothyroidism was confirmed with a low T4 of 5.5 mcg/dL and a high TSH of 20.06 mcIU/mL leading to initiation of levothyroxine. ACTH stimulation test showed peak cortisol level <0.2 mcg/dL, confirming cortisol deficiency. Low aldosterone (<1.0 ng/dL) and high renin (112,568 ng/dL/h) confirmed mineralocorticoid deficiency. Hydrocortisone replacement was started, and fludrocortisone and sodium-chloride supplements were titrated up due to persistently low sodium and high potassium. He was treated for recurrent bacterial infections including MSSA bacteremia, tracheitis, pneumonia, and presumed meningitis, as well as tracheitis/pneumonia with enterobacter, chyseobacterium, and acinetobacter. Genetic evaluation showed normal 46,XY karyotype and negative cystic fibrosis transmembrane conductor (CFTR) sequencing. Microarray (oligo-SNP) demonstrated a 414-kb loss on chromosome 1 resulting in a partial deletion of the OLFM3 gene, which has been suggested as a candidate for glaucoma and not related to any of our patient’s clinical findings. Skeletal survey was obtained due to clinical observation of rhizomelic shortening, but did not demonstrate any abnormalities. The constellation of IUGR, 1° adrenal insufficiency, bilateral cryptorchidism, and characteristic facies prompted suspicion for IMAGe syndrome and specific genetic sequencing looking for mutations in CDKN1C. A blood sample was sent to a Genetic Diagnostic Laboratory at an outside university and revealed a deleterious missense mutation in exon 1 (c.820G>A, p. Asp274Asn) of CDKN1C. This mutation has previously been reported in a patient with IMAGe syndrome (ref Nature Genetics 2012 Jul, 44(7): 788–792).
At 7 months, he had just started rolling over but was not yet sitting. His length was 50th percentile for a 1-month old, and weight was 50th percentile for a 2-month old. Head circumference was ∼2nd percentile. He still appeared to have rhizomelic shortening, and testes were not palpable. He was hypotonic and had severe eczema (Figure 1). At 10 months of age, the patient presented to the emergency department and subsequently died of septic shock complicated by adrenal insufficiency.
Discussion
Previously a clinical diagnosis, IMAGe syndrome can now be diagnosed by CDKN1C gene sequencing. Our patient’s classic findings include IUGR, congenital adrenal hypoplasia with adrenal crises and skin hyperpigmentation, genital anomalies expressed as bilateral cryptorchidism, and characteristic facies. Significant respiratory distress/respiratory failure out of what is expected for gestational age has also been described in previous cases [1, 8]. Metaphyseal or epiphyseal dysplasia were not documented in our patient but characteristically have not presented in neonates. In previous cases, metaphyseal and epiphyseal abnormalities have been diagnosed between 1 and 7 years of age [6, 8]. Skeletal abnormalities have been present at birth in one case, with progression to metaphyseal changes at 19 months [1]. Developmental delay has been reported [4–6]. Pulmonary hypertension has been noted in one previous case; however, it was not as severe as in the case presented here [7]. Unique to his course are findings of congenital hypothyroidism, frequent bacterial infections, and severe eczema, none of which has been previously associated with IMAGe syndrome. Clinical findings are summarized in Table 1A and 1B. Further cases should be investigated to determine if these findings may be part of a broader phenotype associated with IMAGe.
Classic findings |
||||||
---|---|---|---|---|---|---|
IUGR | Adrenal insufficiency | Genital anomalies | Metaphyseal/epiphyseal dysplasia | Dysmorphic facies | CDKN1C mutation | |
Our Patient | Yes | Yes | Yes | No | Yes | Yes |
# of previous patients | 21 | 21 | 14 (every male, no females) | 18 | 21 | 6 |
Associated findings |
Previously unreported findings |
|||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Respiratory distress | Short limbs | Hypotonia | Hypercalcemia/calcuria | Developmental delay | Osteopenia/osteoporosis | Scoliosis | Pulmonary hypertension | Sensorineural hearing loss | Hypothyroidism | Frequent bacterial infections | Eczema | |
Our Patient | Yes | Yes | Yes | No | Yes | No | No | Yes | No | Yes | Yes | Yes |
# of previous patients | 8 | 6 | 6 | 4 | 5 | 3 | 2 | 1 | 1 | 0 | 0 | 0 |
The importance of early recognition of classic clinical features of IMAGe syndrome lies in diagnosing adrenal insufficiency prior to a life-threatening adrenal crisis. Prenatal findings of IUGR and shortened long bones should prompt consideration of IMAGe syndrome and possible postnatal workup for adrenal insufficiency before symptoms manifest. Now that molecular testing is clinically available, the clinician should have a low threshold for testing patients with IUGR and adrenal insufficiency in addition to evaluation for other features of IMAGe syndrome, as this diagnosis will have significant impact on recurrence risk counseling for the family. It is also wise to keep the phenotypic expectations broad as the associated findings may continue to grow with the diagnosis of new patients.
References
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The authors stated that there are no conflicts of interest regarding the publication of this article.
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