Term Neonate With Macrosomia and Coarse Facies: An Overlapping Etiology of Fetal Overgrowth

A male infant is born to a 27-year-old gravida 3, para 1 mother with 2 spontaneous abortions and 1 living child from a planned spontaneous pregnancy to nonconsanguineous parents. The cause of 2 spontaneous abortions has not been evaluated and the older child is 3 years old with normal growth and development.At 38 weeks of gestation, an ultrasonographic evaluation shows polyhydramnios with an amniotic fluid index of 28 and an estimated fetal weight of 4,500 g. There is no history of maternal diabetes, obesity, or exposure to medications, smoking, alcohol, or recreational drugs. No other previous scan reports are available. She is referred to our center for delivery.The infant is born at 39 weeks via cesarean delivery. His birthweight is 4,314 g, length is 52 cm, head circumference is 36 cm, and the ratio of upper to lower segment is 1.6:1. Apgar scores are 9 and 9 at 1 and 5 minutes, respectively, and he does not require any resuscitation after birth. Birth anthropometry on World Health Organization growth charts suggested macrosomia, with all measurements between 2 and 3 standard deviations (SD).Physical examination of the head confirms macrocephaly with 1 × 1.5 cm anterior fontanel without overriding sutures and posterior fontanel admitting the fingertip. The infant has coarse facial features with frontal bossing, bilateral infratemporal hollowing, broad bulbous nose with flat philtrum, hypertelorism, and short broad nasal root, macroglossia with a furrowed tongue, low-set ears, left ear skin tag, thick and everted lower lip, and postaxial polydactyly (left upper and lower limbs) with overlapping toes with a furrow. (Fig 1) There is no hepatomegaly, splenomegaly, or renomegaly, and systemic examination findings are normal. He passes meconium within 24 hours after birth and is exclusively breastfed.Congenital hypothyroidismFetal overgrowth syndromes:A) Beckwith-Wiedemann spectrumB) Simpson-Golabi-Behmel syndromeC) Sotos syndromeInfant of diabetic motherStorage disorder:A) MucopolysaccharidosisB) Lysosomal storage diseasesThe neonate underwent an extensive evaluation for the cause of fetal overgrowth (Table 1).Although genetic studies for fetal overgrowth and evaluation for inborn errors of metabolism had normal results, based on the temporal findings on examination, antenatal ultrasonography, and abnormal thyroid function test results, a final diagnosis of congenital hypothyroidism with clinical Beckwith-Wiedemann spectrum is made (clinical score of 4—macroglossia [2], polyhydramnios [1], birth weight >2 SD above the mean [1]).Overgrowth syndromes are characterized by excessive postnatal growth and tall stature, which is more than an individual’s genetic potential. This can be prenatal, postnatal, or segmental. Prenatal overgrowth, which was seen in this index neonate, refers to those who are born large for gestational age, either macrosomic (>4,000 g) or with length and weight greater than the 97th percentile. (1) These neonates can continue to have accelerated postnatal growth or follow a normal pace. The etiology commonly includes maternal diabetes, Beckwith-Wiedemann spectrum (BWSp), Simpson-Golabi-Behmel, and Sotos syndrome. BWSp is the most common genetic overgrowth syndrome, with a prevalence of 1 in 10,340. (2)Abnormal proliferation of chondrocytes and differentiation into hypertrophic chondrocytes are seen. These are mediated by hormones such as parathyroid hormone–related protein, growth hormone, insulinlike growth factor 1, fibroblast growth factor, and thyroid. (3) Various key causes of overgrowth syndromes seen in the neonatal period are summarized in Table 2.Diagnosis of BWSp is made using the European Network of Congenital Imprinting Disorders scoring system (Table 3). (4) If the neonate has BWSp based on the scoring system but has a negative test result, it is reasonable to refer to a BWSp expert for further evaluation and management. The index neonate has a clinical score of 4 (macroglossia [2], polyhydramnios [1], birth weight >2 SD above the mean [1]).The unique co-occurrence of congenital hypothyroidism and overgrowth has been reported in a few case reports and is often described as primary acquired hypothyroidism. It has been hypothesized that the gene governing the production of thyroxin-binding globulin might be in close proximity to the one that governs the production of thyroxin and also to the gene suppressing the manifestations of BWSp. (5) Congenital hypothyroidism was reported in another case of a neonate with Sotos syndrome. (6)In infants with suspected BWSp, the first-tier test is a methylation study which may show a gain of methylation on IC1 (maternal), loss of methylation on IC2 (maternal), or both (paternal UPD); or a loss of chromosomal segment on 11p15.5 (along with its proper methylation) in nearly 75% cases. (4) If the methylation study is negative, sequence analysis or gene-targeted deletion-duplication analysis of CDKN1C for loss of function on the maternal allele will detect ∼5% of cases with no family history and ∼40% of cases with positive family history. (4) Karyotype may pick cytogenetic duplication, inversion, or translocation of 11p15.5 in less than 1% of cases. (4) However, a chromosomal array (single nucleotide polymorphism based) can pick small chromosomal deletions and duplications in ∼20% of cases. (4) When peripheral blood sample test results are negative, other tissues such as saliva, skin, or the hypertrophied tissue may identify low-level mosaic genetic and epigenetic changes within 11p15.5 in up to 10% of affected patients. (7)Short-term complications include the risk of hypoglycemia and macroglossia-related feeding difficulty, the risk of apnea, and persistent drooling. In the long term, the current guidelines of the American Association of Cancer Research recommend uniform surveillance for all overgrowth syndromes with an increased propensity for Wilms tumor (WT) and hepatoblastoma. (8) The overall risk of malignancy among BWSp patients is approximately 7.5%: 4% WT, 1% hepatoblastoma, 0.5% rhabdomyosarcoma, 0.5% neuroblastoma, and ∼1.3% all other tumors. (4)(9) α-fetoprotein (AFP) testing is currently lacking in the international consensus statement as infants with BWSp often have higher AFP levels. (7) The neurocognitive development of BWSp patients is similar to that in the general population, and therefore no additional surveillance is recommended for development. (10)The infant has no complications during the hospital stay, is exclusively breastfeeding at the time of discharge, and receives close follow-up by pediatrics genetics. At 3 months and 6 months of follow-up, the coarse facial features and dysmorphism persist. Repeat abdominal ultrasonography shows no evidence of organomegaly and thyroid function tests have normalized with thyroid supplementation at 10 µg/kg per day. The infant continues to exclusively breastfeed, with weight, length, and head circumference between 2 and 3 SD with normal development and continues to receieve close monitoring.Fetal overgrowth syndromes such as the BWSp present with inherited health concerns and risk of tumor predisposition necessitating prompt diagnosis at the earliest suspicion.The association of congenital hypothyroidism leads to overlapping clinical findings because of the complex interplay of genetic, epigenetic, and hormonal factors in growth, which complicates the diagnosis.A combination of methylation studies, karyotype, and clinical exome sequencing might still underdiagnose those with BWSp, and these infants are required to be followed up closely for growth and risk of malignancy.American Board of Pediatrics Neonatal-Perinatal Content SpecificationsRecognize the diagnostic implications of single vs. multiple anomalies.Know the indications, limitations, and techniques for newborn screening for genetic disorders.Know the clinical features and inheritance patterns of common syndromes or associations that can be recognized in the newborn period (eg, VATER [vertebrae, anus, trachea, esophagus, and limbs) association and DiGeorge syndrome).Know the disorders for which molecular genetic studies are clinically indicated, such as cystic fibrosis, and how to interpret test results.The authors thank Dr Sangeeta Ravat, Dean, Seth GS Medical College, and KEM Hospital, Mumbai, India, for granting permission for publication.

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