Late-presenting congenital diaphragmatic hernia in a child with TMEM70 deficiency.

Abstract

Transmembrane protein 70 (TMEM70) deficiency has been delineated as a distinct mitochondrial disease less than a decade ago (Cízková et al. 2008). Hallmarks of the disease include hypotonia, developmental delay, hypertrophic cardiomyopathy (HCM), facial dysmorphism, microcephaly, hypospadia, lactic acidosis and 3-methylglutaconic aciduria (3MGA). Although there is no curative treatment, proper management of hyperammonemic metabolic crises seems to be crucial for the prognosis of these patients. Characteristic facial features with high forehead, down-slanting palpebral fissures, curved eyebrows, prominent nasal bridge, low-set ears, thin lips, microretrognathia and ptosis have been described in two-thirds of patients. The disease is panethnic but particularly common in the Roma population with prevalent c.317-2 A > G mutation (Spiegel et al. 2011, Magner et al. 2015). Congenital malformations in patients with TMEM70 deficiency include heart defects (36%) with valve defects and aortic coarctation, hypospadia (50% of affected boys), umbilical and inguinal hernias (approximately one-third of cases), syndactyly between the second and third finger, congenital cataract, and agenesis or hypoplasia of corpus callosum (Spiegel et al. 2011, Magner et al. 2015). Congenital diaphragmatic hernia (CDH) has been described only in one patient with this disease, so far (Catteruccia et al. 2014). We report herein the second case of unique association of TMEM70 deficiency and CDH. Severe lactic acidosis and HCM were noted in a boy of Roma ethnicity in the neonatal period. Microcephaly, hypotonia and dysmorphic facial features (synophris, curved eyebrows, anteverted nostrils, low set ears, microretrognathia), but no hypospadia, were observed later in infancy. Chest radiograph made at the age of one year did not show presence of diaphragmatic hernia. At the age of 3.5 years, the boy was admitted to hospital due to vomiting and somnolence. Physical exam revealed tachycardia, tachypnoea and decreased breathing sounds on the left side of the chest. Chest radiograph showed hydroaeric levels at the left thoracic side (Fig. 1A). Upper gastrointestinal series with small bowel follow-through showed normally positioned esophagus and stomach, whereas duodenum ascended towards the left part of the chest cavity, which was filled with intestinal loops (Fig. 1B). Posterolateral left Bochdalek hernia with defect diameter of 5 cm and hernial sac protruding to the chest cavity was visualized during surgical intervention. The whole jejunum and ileum, including the ileocecal valve, was herniated. After repositioning of the abdominal organs, plastic of diaphragm and Ladd procedure followed. Twelve months later, the boy succumbed to severe metabolic crisis with lactic acidemia but absent 3MGA. Unfortunately, ammonia level was not measured at the time. Post-mortem mutation analysis of TMEM70 in the patient's DNA sample documented homozygous mutation c.317-2 A > G. Associated congenital anomalies are found in 8.6% of patients with late presenting CDH, cardiac anomalies being the most frequent (Bagłaj 2004). In dual-hit hypothesis of CDH evolution, a primary bilateral lung hypoplasia results from combined genetic and external factors, while the second hit affects only the left lung by pressure of intrathoracic bowels (Keijzer et al. 2000). Although the lung hypoplasia was described in one patient with TMEM70 (Spiegel et al. 2011), there was no proof of hypoplastic lungs in our patient or in the patient reported by Catterucia et al. (2014). Hypoplastic lungs may cause the persistent pulmonary hypertension in newborn (PPHN), which is frequently observed in children with TMEM70 (>50%). However, this finding has probably no relation to the reported CDH (Catteruccia et al. 2014). The second case, reported herein, further supports the association between TMEM70 deficiency and CDH, which might help to diagnose this rare but treatable disorder. The work was supported by RVO-VFN64165/2012 and PRVOUK P24/LF1/3. Authors do not have conflicts of interest to report.