Short rib-polydactyly syndrome (Saldino-Noonan type) undetected by standard prenatal genetic testing

Case report

A 3030-g girl was born at 37 weeks’ gestation to a healthy 17-year-old Hispanic mother (gravida 1, para 0) via emergency cesarean section due to non-reassuring fetal heart tones. The 19-week anatomy scan initially raised concern for skeletal dysplasia, demonstrating shortened long bones and polyhydramnios, without mention of extra digits or situs inversus (stomach was noted to be on the left on multiple sonograms). There were also concerns for a coarctation of the aorta and hydrops fetalis. A referral was made to maternal-fetal medicine, a clinical genetic counselor, pediatric cardiology and neonatology.

The working differential diagnoses included; aneuploidy, congenital infections and achondroplasia/chondromalacia. At this time, based on the clinical information available, the decision was made to order the skeletal dysplasia genetic panel as opposed to whole exome sequencing (or a comprehensive panel for ciliopathies). Maternal peripheral blood and cultured amniocytes from the fetus were analyzed with the next generation sequencing (NGS) skeletal dysplasia genetic panel consisting of the ten most common genes for skeletal dysplasia: COL1A1, COL1A2, COL2A1, COMP, SLC26A2, FGFR3, FLNA, HSPG2, SOX9 and TRPV4. This testing returned negative. Evaluation was also negative for common congenital infections (cytomegalovirus, parvo virus and toxoplasmosis).

At delivery, the infant was grossly dysmorphic with the poor respiratory effort and marked cyanosis. She was intubated and placed on high-frequency oscillatory ventilation. Initial chest X-ray revealed a dysmorphic thoracic cage with severely hypoplastic lungs. Throughout her admission, her respiratory status steadily declined, prompting increases in ventilator support. A skeletal survey revealed features consistent with short rib-polydactyly syndrome (SRPS). An echocardiogram showed mild right ventricular hypertrophy with a large patent ductus arteriosus. The patient’s labs showed mild thrombocytopenia of undetermined etiology with a platelet count ranging from 110,000 to 150,000 K/μL. On the 7^th day of life, her oxygen requirement escalated to 100% on maximal ventilator settings. Due to the patient’s poor prognosis and continued respiratory decompensation, the family decided to redirect care towards comfort measures. The immediate cause of death in this infant was hypoxemia secondary to lung hypoplasia and heart abnormalities, secondary to the SRPS.

Postmortem examination (Figure 1) revealed features consistent with SRPS including shorted ribs and extremities, postaxial polydactyly, a short cranial base with a bulging forehead and saddle nose, and hydrops fetalis. The proximal upper and lower extremities appeared severely shortened with seven digits on the left hand, six digits on the right, seven toes on the left foot with syndactyly of the 5^th and 6^th toes, and six toes on the right foot.

Figure 1:

Autopsy findings.

(A) Full body of infant supine note shape of thorax and ratio of trunk length to limb lengths; (B) rib cage after internal organs were removed, note shape of rib cage; (C) lungs, anterior aspect, note abnormal lobation, situs inversus, with left middle lobe and right lingula present; (D) left hand, note seven digits; (E) left foot, note extra digit and duplication of fifth at interphalangeal joint; (F) right hand, note six digits.

The thoracic cage revealed 11 pairs of ribs, with the first rib missing bilaterally. The lungs weighed 20 g (normal 42–68 g) with a lung weight/body weight ratio of 0.007 (<0.012 at term is consistent with pulmonary hypoplasia). At 37 weeks, the lungs are normally in the alveolar stage of development. Microscopically, the infant’s lungs were arrested in the saccular stage of development. Additionally, there was situs inversus, with the left lung having three lobes and the right lung having two and a lingula.

The heart was abnormally rotated to the left with a patent ductus arteriosus (1 mm in diameter), coarctation of the aorta, and an atrial septal defect (2 mm in diameter). The peritoneal cavity contained 40 mL of serosanguinous fluid and there was marked edema in the kidneys. In addition, the liver displayed significant microsteatosis, fibrosis and cholestasis.

DNA from the infant was subsequently sent for further genetic studies, for the Skeletal Dysplasia Ciliopathy Panel NGS to test for Saldino-Noonan type, and sequencing of an additional 19 genes was performed. Results from this analysis were correlated with the amniocentesis DNA sample from the previous genetic analysis and revealed four heterogeneous alterations: DYNC2H1 exon 38 and 42, IFT172 exon 43, TTC21B exon 19. The patient had a compound heterozygous mutation in the DYNC2H1 gene on chromosome 11q22, resulting in SRPS [1]. The family history was only significant for mother’s half-sister’s son with isolated fetal shortening of the lower extremities noted on prenatal ultrasound. Upon delivery this infant was only noted to have scoliosis, and he is doing well without any issues with mobility.

Discussion

SRPS represent a group of autosomal recessive perinatally lethal syndromes characterized by short limbs, short horizontal ribs, a narrow thorax (Figure 2) and a variable degree of polydactyly (Figure 3). Four types have been distinguished: Type I (Saldino-Noonan type), Type II (Majewski type), Type III (Verma-Naumoff type) and Type IV (Beemer-Langer type) [2]. SRPS can be diagnosed by three-dimensional ultrasound as early as 13 weeks and confirmed by molecular testing. Lethality can be evaluated by chest to abdominal circumference ratio or femur length to abdominal circumference ratio [3]. The exact incidence of SRPS is unknown due to the rarity of the disease. Differential diagnoses include other well-described lethal and non-lethal skeletal dysplasias such as Ellis-Van-Creveld syndrome, Jeune syndrome, thanatophoric dysplasia, osteogenesis imperfecta and chondrodysplasia [4].

Figure 2:

Chest X-ray obtained immediately after birth.

Extremely small thorax, small ribs (thoracic dystrophy) and pulmonary hypoplasia.

Figure 3:

Long bones X-ray (upper and lower extremities).

Short bones of the hands and feet. Significant metaphyseal dysplasia of the long bones and polydactyly.

SRPS is caused by genetic mutations that affect the function of primary cilia, which are microtubule-based projections that receive and integrate signaling inputs on almost all cells. The intraflagellar transport (IFT) genes regulate a bi-directional microtubule-based transport system that traffics cilial components in and out of the axoneme. The IFT system requires motor proteins, including the heavy chain of cytoplasmic dynein two complexes encoded by the DYNC2H1 gene, to transport the molecules required for ciliogenesis [5]. DYNC2H1 is the most commonly involved locus in SRPS and has been associated with SRP type 1, 2, 3, as well as non-lethal asphyxiating thoracic dystrophy [6].

Endocardial cushion defects, hydrops fetalis, postaxial polydactyly, pulmonary hypoplasia and fluid collections with edema are additional findings seen in this infant which are most consistent with SRPS Type I. With SRPS Type I, a small chest cavity size prevents the patient’s lungs from developing fully, rendering respiratory effort extremely difficult. Type II displays both preaxial and postaxial polydactyly, as well as facial findings, such as cleft lip or low-set ears. Type III is very similar to type I SRPS, but has a better mineralized appendicular skeleton, and death is usually due to asphyxia rather than pulmonary hypoplasia. Type IV often does not present with polydactyly, and tibia shortening is less prominent than in other types [7], [8]. The current guidelines for fetal detection of skeletal dysplasia were published by Krakow et al. [9] and involve the use of two or three-dimensional ultrasound and molecular genetic testing. Given the multitude of genes involved in skeletal dysplasia, in this case, additional testing with 19 other genes was needed to identify the causative mutation.

This case presentation emphasizes that skeletal dysplasias are rare with variable presentation and a multitude of potential genetic mutations. Standard prenatal ultrasound may raise the suspicion for skeletal dysplasia. However, confirmation of the diagnosis prior to birth requires more sophisticated imaging (e.g. three-dimensional ultrasound), and due to the many potential mutations causing SRPS, comprehensive genetic testing may be needed. Prenatal diagnosis may have better prepared the family for dealing with complex decision making. It is our hope that the postnatal genetic and anatomic (autopsy) confirmation will assist this young mother in planning for future pregnancies.