Severe, neonatal onset mitochondrial disorders (MitD) are difficult to diagnose and cause substantial strain on patients and caregivers. This study explores the value of Early Whole Exome Sequencing (eWES), an expensive, last-line diagnostic, relative to the current standard of care (SOC) for the diagnosis of newborns suspected of having a severe MitD. We conducted a cost-effectiveness analysis from the US societal perspective, using a hybrid decision tree Markov model, over a 25-year time horizon and an annual 3% discount rate. Parameters were populated using published literature values of comparable disease states, expert opinion and the Pediatric Health Information System database, which collects inpatient encounter data from 47 U.S. children’s hospitals. Incremental cost-effectiveness ratios and incremental net monetary benefits (iNMB) were calculated relative to the SOC. One-way sensitivity analyses, probabilistic sensitivity analyses (PSA) and cost-effectiveness acceptability curves were also generated. INMBs of eWES relative to SOC at a willingness to pay (WTP) of $50,000 and $200,000 per quality-adjusted life year for the base case were $24,888 and $25,200, respectively. eWES, SOC diagnostic probabilities and neonatal intensive care unit length of stay were revealed as important parameters driving base case results. PSA revealed that eWES had a 68% likelihood of being cost-effective at a WTP of $50,000, a 74% likelihood of being cost-effective at $200,000 and 66% likelihood of being cost-effective at $0. EWES dominates SOC in diagnosing patients suspected of having a MitD. As the WTP threshold increases, eWES increasingly becomes more likely to be cost-effective relative to SOC, indicating that the mechanism of cost-effectiveness is cost-minimization. Our findings demonstrate this current wave of innovative sequencing is a cost-effective measure for diagnosing severe MitD in select neonates, while also highlighting future research necessary to determine the value of genetic diagnostics for MitD neonates.

Generalized arterial calcification of infancy (GACI) is a rare genetic disorder with high infantile mortality, described to be due to ENPP1, and less commonly ABCC6 mutations. Bisphosphonate treatment has been described to improve survival in ENPP1-positive GACI patients, but few studies have described bisphosphonate treatment in ABCC6-positive patients. Without therapy, patients will die before 6 months of age. Our patient is now 3 years old, former recipient twin of twin-to-twin transfusion syndrome (TTTS). Initial fetal echocardiogram at 19 weeks showed calcifications of the ascending aorta and pulmonary artery (PA). She underwent utero laser therapy, and despite resolution of the TTTS, her follow-up scans showed progressive calcification of the aorta and PA. Postnatal echocardiogram showed calcification and supravalvar stenosis of the aorta and PA. CT on day of life 6 showed calcifications in the PAs, aortic arch, and descending aorta. Quantification of valvular calcification can be difficult; in our patient, increasing outflow tract gradient on echocardiogram was used to monitor disease progression. Molecular testing revealed an ABCC6 gene mutation. She was started on weekly IV pamidronate (0.1–0.3 mg/kg/week) on day 8 of life then transitioned to oral etidronate (15–20 mg/kg/day). Given progressive supravalvar aortic and pulmonary stenosis, she underwent surgical repair with patch augmentation of the PA and ascending aorta at 4 months old. She has done well post-operatively, continuing on enteral bisphosphonate therapy with no side effects to date. Her identical twin was confirmed to have the same mutation and remains asymptomatic with no calcifications. Aggressive bisphosphonate therapy should be started as soon as possible in patients with infantile arterial calcinosis due to ABCC6 or ENPP1 mutations. Echocardiographic evaluation can be used to monitor disease progression by arterial gradients. Molecular testing is also essential to evaluate for possible co-morbidities in these patients and pregnancy management for the future.

DEAR EDITOR, The ichthyoses are rare skin disorders linked by the common finding of scale and concomitant barrier function abnormalities. Recently, mutations in PNPLA1, which encodes patatin-like phospholipase domain containing 1 and plays a role in the formation of the epidermal lipid barrier, have been identified as a rare cause of nonsyndromic autosomal recessive congenital ichthyosis (ARCI). We identified patients with PNPLA1 mutations within our registry of 732 ichthyosis kindreds. DNA was isolated from blood, and either multiplex targeted next-generation sequencing of 42 genes known to cause disorders of keratinization, or whole-exome sequencing was performed (Appendix S1; see Supporting Information). Fourteen unrelated probands with ARCI were found to be compound heterozygous or homozygous for mutations in PNPLA1,which were confirmed with Sanger sequencing. PNPLA1 mutations segregated with disease in all kindreds, five of which were consanguineous (Figs S1–14; see Supporting Information). In total 16 different PNPLA1 mutations were observed, including two that result in early termination, a splice-site mutation and 13 missense substitutions at conserved residues (Fig. 1g and Fig. S15; see Supporting Information). All missense mutations are within the more highly conserved N-terminal half of the protein, and all but two are clustered within the patatin domain. Two patients are homozygous for missense mutations at S53, the nucleophilic serine in the putative lipid hydrolase site, and one is homozygous for a missense mutation at D172, the other critical residue in the catalytic dyad. The phenotypes of all patients with PNPLA1 mutations are described in Table 1, with representative clinical photos provided in Figures S1–14 (see Supporting Information). At birth, seven patients presented with a collodion membrane (one with vernix-like hyperkeratosis), and eight showed generalized erythema and/or scaling. Mature phenotypes included scale that was fine or plate like, and erythema ranging from minimal to severe (Fig. 1a–f). The presence and degree of ectropion and palmoplantar keratoderma are variable, although they are either absent or mild in the majority of patients. Only seven of 19 patients were born with a collodion membrane. Generally, the spectrum of phenotypic severity appears difficult to correlate with specific PNPLA1 genotypes. While some patients with the same genotype exhibit consistent clinical features, there are others with identical or similar mutations who show notable variation in phenotype. For instance, the affected siblings of kindred ICH162 (Fig. S2; see Supporting Information), both of whom are compound heterozygous for the same missense mutations, vary significantly in the severity of their presentations. ICH162-1 was born collodion and developed plate-like scale, palmoplantar keratoderma and severe ectropion, whereas her sister had generalized scale and erythema at birth with no collodion membrane, and now has fine white scale; mild ectropion presented only within the past 2 years at age 80 years. Interestingly, we report two families that appear to display dominant inheritance, but in which sequencing revealed PNPLA1 mutations consistent with recessive inheritance. In kindred ICH201 (Fig. S3; see Supporting Information), which was previously published as having autosomal dominant ichthyosis, there are actually two different recessive PNPLA1 genotypes in affected individuals. The proband (ICH201-1) is compound heterozygous for A34T and S140P, while her two affected children (ICH201-3 and ICH201-4) are both homozygous for S140P, having presumably inherited a second copy of this mutation from their unaffected father. Mutation A34T has previously been observed with homozygous inheritance in a report of a kindred from Galicia, Spain. Kindred ICH201 is also from Galicia, and collection of the extended family history revealed additional family members with ichthyosis (the proband’s deceased sister and a deceased nephew from another sister), despite no known history of consanguinity. These observations suggest that A34T and S140P may be founder mutations present at low frequency in Galicia, a region in which founder mutations in TGM1 have also been reported. Kindred ICH454 (Fig. S7; see Supporting Information) is also notable for an affected parent with two affected children and the resulting appearance of dominant inheritance. In this family, all three are homozygous for the same PNPLA1 mutation as a result of the consanguineous union of the proband and a first cousin who is a heterozygous carrier. Two of the missense mutations we report are distal to the patatin domain (amino acids 16–185, Fig. 1g). Mutation C216R is homozygous in the three affected members of kindred ICH454 (described above), and mutation P235L is homozygous in patient ICH592-1, a child of first cousins of

A 41-year-old-white man with achondroplasia has been followed intermittently since age 27. During this time, he has complained of neck and back pain with limited mobility in both. Other problems have included temporomandibular joint pain, dysuria without apparent urinary tract infection iritis, anemia, and an elevated gamma globulin fraction. Recently he returned to the clinic complaining of rigidity of the entire spine. Radiographs showed complete fusion of the sacroiliac joints and fusion of the cervical vertebral bodies and apophyseal joints, consistent with ankylosing spondylitis. He was found to be HLA B-27 positive. This case illustrates the importance of considering other diseases whenever atypical orthopedic problems arise in patients with a bone dysplasia.