Lethal skeletal dysplasia detected by antenatal ultrasound: Achondrogenesis type II

INTRODUCTION

Fetal skeletal dysplasia comprises around 400 genetic disorders that result from widespread disturbance in skeletal development beginning in the fetal period. Lethal skeletal dysplasias are associated with very poor prognosis as such fetuses die in utero or soon after birth.^[1,2]

Antenatal ultrasound can detect skeletal dysplasia in the late first trimester or early second trimester and predict its lethality. Encountering findings of limb shortening or poor ossification of the spine warrants detailed examination of the fetus to rule out or confirm the possibility of skeletal dysplasia. Following termination of pregnancy, a detailed evaluation of the abortus should also be done.

However, determining the specific type of fetal skeletal dysplasias in routine clinical practice is a tough challenge as it includes a group of heterogeneous genetic conditions having a wide spectrum of often overlapping phenotypes. They may often arise de novo without prior family history. The chance of recurrence, though rare, necessitates genetic testing, counseling, and close follow-up of future pregnancies. Here, we describe a case of lethal skeletal dysplasia detected by early second-trimester ultrasound.

CASE REPORT

A 24-year-old primigravida, having regular cycles, with no known comorbidities, no history of known genetic disorders in the family, non-consanguineous marriage, who had her gestational age confirmed by an earlier dating scan, visited our center at 15 weeks 1 day gestation with non-specific abdominal pain. Antenatal ultrasound revealed a single live intrauterine fetus with fetal biometry is as follows: Biparietal diameter (BPD) of 2.9 cm (15 weeks 3 days) – 87^th centile; head circumference: 11.5 cm (15 weeks 4 days) – 81^st centile; abdominal circumference (AC): 8.6 cm (14 weeks 4 days) – 23^rd centile; and femur length (FL): 0.8 cm (12 weeks 3 days) – 1^st centile. Nuchal fold thickness was mildly increased (3.1 mm) and nasal bones were visualized. All long bones were found to fall <5 percentile for gestational age with bowing of the femur and tibia. FL/AC ratio was 0.09, and the findings were suggestive of lethal skeletal dysplasia. Poor vertebral body ossification was also noted [Figure 1]. Tiny oval cysts were noted on the lateral aspect of the neck. The differential diagnoses for fetal neck cysts include cystic hygroma, branchial cleft cyst, lymphatic malformation, dermoid, and epidermoid cyst.

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Figure 1: Antenatal ultrasound images showing poor ossification of spine (green arrows) and measurement of nuchal translucency (calipers).

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A multidisciplinary team discussion including a radiologist, an obstetrician, and a fetal medicine specialist was done and formal genetic counseling was conducted by a geneticist. The patient was informed in detail about the possibility of lethal skeletal dysplasia in the fetus, the chance of survival of the fetus, its sporadic nature, and the need for genetic testing including mutational analysis, considering the possibility of carrier state in parents and possibility of recurrence in subsequent pregnancies.^[3] The patient opted for medical termination of pregnancy, which was performed at 16 weeks of gestation. The delivered male fetus weighed 64 g and had a relatively large head, protuberant abdomen with loose skin, and bowing of both lower limbs [Figure 2].

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Figure 2: Gross specimen of abortus at postmortem examination.

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Antero-posterior [Figure 3a] and lateral view X-ray [Figure 3b] of the fetus were acquired soon after expulsion which revealed a poorly ossified skull with well-formed facial bones. A small radiolucent area was noted in the right parietal calvarium. Radiolucent areas were noted along the posterior aspect of the neck and upper thorax – likely cysts. Only few neural arch ossification centers were seen in the cervical region, and approximately 5 vertebral ossification centers were seen at the thoraco-lumbar junction. Eleven pairs of shortened ribs were noted with few showing cupped ends, with no evidence of fracture or beading. The scapula was small in size. The iliac bone was hypoplastic with concave inferior margin, whereas ossification centers for the ischium and pubic bones were absent. The fetus had severe tetra micromelia with bowing of the femur and tibia with metaphyseal widening and spurs at the end of long bones. Metacarpals, metatarsals, and proximal and distal phalanges were visualized. The above features were suggestive of achondrogenesis type II.^[1,2]

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Figure 3: (a and b) X-ray (a) Anteroposterior view post expulsion: Large head (red arrow), narrow chest, protuberant abdomen, poorly ossified skull vault, well ossified facial bones, poor ossification of spine (yellow arrow), 11 pairs of short ribs, few with cupped ends, small dysplastic clavicle and scapulae, hypoplastic ilium with inferior concavity (white arrow), absent ischium and sacrum, severe tetra micromelia, mild metaphyseal widening, metaphyseal spurs, bowing of femur (green arrow) and tibia. (b) Lateral view post expulsion: Loose subcutaneous tissue in scalp and neck (orange arrow), rounded radiolucent area in right parietal scalp / calvarium (red arrow), radiolucent areas posterior aspect of neck - likely cyst (blue arrow). Absence fracture or callus also noted.

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At autopsy, the fetus showed a relatively large head, protuberant abdomen, and all long bones were found to fall short of the 5^th percentile. Both femur and tibia showed bowing with shortening of all four limbs. Few cysts suggestive of cystic hygromas were seen in the neck – a feature of achondrogenesis. Internal organs were grossly normal except right renal ptosis, which was likely an incidental finding. All orifices were patent, no cleft palate was seen, and the external genitalia were normal. Histopathological examination of lungs revealed pseudo-glandular and canalicular pattern, seen at 16 weeks of gestation with reduced interstitial tissue and mild congestion. Histopathology of the rest of the internal organs was unremarkable; only changes expected in early gestation were seen. Histopathologic evaluation of the resting cartilage revealed high cellularity, reduced cartilage matrix, large lacunae, and increased vascularity of cartilage – consistent with Achondrogenesis type II. Karyotyping was performed and was normal (46, XY). Karyotyping of both parents was also performed which was normal. Further genetic tests were suggested, but the patient decided against it, considering the low risk of recurrence (<1%),^[3] uncertain role of molecular testing in a sporadic type skeletal dysplasia if detected for the first time in the present pregnancy^[3] and financial and logistic constraints. She was kept on follow-up and was advised formal genetic counseling before the next pregnancy, early ultrasound screening for signs of skeletal dysplasia with the aid of three-dimensional ultrasound or magnetic resonance imaging if needed, and genetic testing of the fetus with chorion villus sampling or amniocentesis by direct mutational analysis or linkage analysis.

DIFFRENTIAL DIAGNOSIS

The common differential diagnoses include achondrogenesis, thanatophoric dysplasia, achondroplasia, congenital hypophosphatasia, campomelic dysplasia, and short limb polydactyly syndrome. In this case, poor ossification of the spine, absence of fractures, abnormalities in pelvic bones, absence of cleft palate, and absence of visceral involvement along with histopathologic features are suggestive of achondrogenesis type II.

DISCUSSION

Fetuses with lethal skeletal dysplasias are a heterogeneous group of over 400 conditions and are generally associated with poor outcome; they either die in utero or soon after birth. Lethal skeletal dysplasias can be detected as early as 13 weeks by antenatal ultrasound. The indicators of lethality in antenatal ultrasound are FL/AC ratio <0.16, thoracic circumference (TC)/AC <0.89 TC, and TC <5^th centile, especially when the BPD being normal, femur to foot ratio (<1).^[4,5] Hypoplasia of the thorax, bowing or fractures, short ribs, caudal regression, and cloverleaf skull may also be seen in ultrasound. By postnatal radiographs, common skeletal dysplasias can be recognized through pattern recognition.^[2] The babygram or whole-body radiograph includes anteroposterior and lateral radiographs of the full body length.

Achondrogenesis is characterized by poor ossification of skull and spine, tetra micromelia, and nuchal edema small iliac bones with inferior concavity (“parachute” or “hand glider” sign).^[1] Achondrogenesis type I occurs due to mutation of SLC26A2 and TRIP11 genes and is more severe, characterized by multiple fractures and widening of the lumbar interpediculate distances (“cobra-head” sign). Achondrogenesis type IA (Houston-Harris) is characterized by the absence of ossification of the skull and vertebral bodies, short horizontal flared ribs, multiple fractures, and extremely short long bones, especially the femur, radius, and ulna. Type IB (Parenti-Fraccaro) shows a poorly ossified skull, ossified vertebral pedicles with a trapezoid configuration of femurs. Achondrogenesis type II (Langer– Saldino syndrome) with an incidence of 0.2/100,000 births occurs due to a mutation in COL2A1 gene and is characterized by the absence of fractures.^[6]

The other common lethal skeletal dysplasias that demonstrate pulmonary hypoplasia and severe micromelia include thanatophoric dysplasia, achondroplasia, and congenital hypophosphatasia.^[1,3] Thanatophoric dysplasia is characterized by severe platyspondyly, decreased caudal inter-pediculate distances, and French telephone receiver-shaped, bowed, short femurs.^[7] Osteogenesis imperfecta is characterized by multiple fractures with callus formation, angular deformities, beading of ribs, and abnormal skull shape. X-ray in hypophosphatasia shows under – ossification of vertebrae and neural arches, absent pedicles and bodies of the vertebrae, and absent ossification of the pelvis.

Campomelic dysplasia is another lethal skeletal dysplasia caused by a mutation in SOX-9 gene and is characterized by Pierre Robin sequence, cleft palate, respiratory compromise, and ambiguous genitalia or normal female external genitalia. Short limb polydactyly syndrome is an autosomal recessive lethal skeletal dysplasia showing horizontally located short ribs, polysyndactyly, micromelia, short ovoid tibiae, and sometimes visceral involvement.

There have been four cases of achondrogenesis previously reported from India.^[8-10] Post-delivery clinical and radiological examination, genetic testing, and histopathological examination should be conducted in all suspected cases. If possible, preservation of tissue samples for DNA analysis considers the possibility of recurrence in subsequent pregnancies. If genetic tests are not accessible and acceptable to the patient, as in our case, post-abortion radiographs can help in gaining clarity in diagnosis.

CONCLUSION

This case report emphasizes the role of antenatal ultrasound in early detection of skeletal dysplasia, predicting its lethality and the need for multidisciplinary approach and genetic counseling in the management of these pregnancies. This case also throws light into the critical role of post abortion radiograph as a key tool in pattern recognition which can suggest the type of skeletal dysplasia and aid in further management. This is especially important in case genetic testing is not conducted, and radiographs can be obtained in any low-resource setting.

TEACHING POINTS

• Limb shortening and poor ossification of the spine are often the common findings which suggest the possibility of skeletal dysplasia.

• Predictors of lethality in skeletal dysplasia in antenatal ultrasound are FL/AC ratio <0.16, TC/AC <0.89 TC, and TC <5^th centile, especially when the BPD is normal, femur to foot ratio (<1).

• Critical components of patient management in suspected skeletal dysplasia include thorough skeletal assessment, multidisciplinary team approach, post-abortion fetal radiographs, autopsy and histopathologic examination, genetic counseling, genetic testing, and guidance for surveillance of future pregnancies.

MCQs

1. Which genetic mutation causes achondrogenesis type II?

   1. COL2A1 gene

   2. SOX-9 gene

   3. SLC26A2 gene

   4. TRIP11 gene

   Answer key: a

2. Which of the following is not a feature of achondrogenesis type II?

   1. Bowing of long bones

   2. Poor ossification of the spine

   3. Multiple fractures

   4. Tetra micromelia

   Answer key: c

3. Which of the following is not an integral part of the management of suspected fetal skeletal dysplasia?

   1. Genetic counseling and genetic testing

   2. Post-abortion radiograph

   3. Multidisciplinary team management

   4. None of the above

   Answer key: d

4. Which genetic mutation causes achondrogenesis type I?

   • COL2A1

   • SOX-9

   • SLC26A2 and TRIP11

   • APC

   Answer: c

5. Which among the following is not a lethal skeletal dysplasia?

   • Thanatophoric dysplasia

   • Achondrogenesis

   • Campomelic dysplasia

   • Achondroplasia

   Answer: d