American Journal of Medical Genetics 41:417-422 (1991)
Generalized Chondrodysplasia Punctata With Shortness of Humeri and Brachymetacarpy: HumeroMetacarpal (HM) Type: Variation or Heterogeneity? Zvi Borochowitz Simon Winter Center for Human Genetics, Bnai-Zion Medical Center, Technion-Faulty of Medicine, Haifa, Israel
We report on a girl with symmetrical rhizomelic shortness of the upper limbs and punctate epiphyseal calcifications noted at birth. Presumably she has normal height, but short nose, short hands, and normal mentation; and on roentgenograms short and wide humeri, symmetrical brachymetacarpy, especially of the 4th metacarpals, and hypoplastic distal phalanges, sagittal clefting of vertebral bodies, and punctate calcificationsat various areas including the entire spine, sacrum, hands, feet, trachea, and thyroid cartilage. It is an apparently new syndrome of chondrodysplasia punctata (CP), quite distinct from the classic form (Conradi-Hunermann type), as well as the other well-definedforms of CP. We thus suggest the term chondrodysplasia punctata, humero-metacarpal (HM) type. KEY WORDS chondrodysplasia punctata, punctate epiphyseal calcifications, short humeri, short metacarpals, skeletal dysplasia INTRODUCTION We report on an apparently undescribed variety of symmetrical rhizomelic upper limb dysplasia with punctate epiphyseal calcifications. This is a sporadic case, appears to represent a previously apparently undescribed form of CP, quite distinct from the classic form (Conradi-Hunermann type) [Spranger et al., 19711, as well as other forms of CP and variety of other diseases (Table I) [Gilbert et al., 1976; Happle, 1977, 1980; Burck, 1982; Badois et al., 1983; Curry et al., 1984; Pauli et al., 1987; Burton and
Received for publication May 24, 1990; revision received April 19, 1991. Address reprint request to Dr. Z. Borochowitz, Director, Simon Winter Center for Human Genetics, Bnai-Zion Medical Center, Box 4940, Haifa 31048, Israel.
0 1991 Wiley-Liss, Inc.
Oestreich, 1988;Maroteaux et al., 1989;Lawrence et al., 1989; Rittler et al., 19901.
CLINICAL REPORT The girl was the second child born to her AshkenaziJewish parents. Consanguinity was denied. The mother, age 26, was known to have an uncomplicated insulindependent diabetes mellitus (IDDM)onset at the age of 16 years. Therefore both of her pregnancies were monitored carefully in a tertiary maternal-fetal center. A healthy boy was the outcome of the previous, uncomplicated pregnancy. The father, age 28, was healthy. No other individuals in either family were known to have IDDM, short limbs, or any genetic disorder. Maternal diabetes was well controlled from the beginning and throughout this pregnancy. Maternal hemoglobin Al, level was below 8.5%since early pregnancy and was consideredwithin the accepted normal range for a teratogenic risk [Miller et al., 19811. At 7-8 weeks of gestation the mother developed mild varicella zoster (VZ). It was diagnosed by the presence of a few varicella eruptions found on her upper limbs, chest, and face. Body temperature was above normal only during the first day of illness, rising to a maximum level of 38.2"C. Genetic counselling mainly emphasized IDDM and early-gestational varicella zoster. The couple elected to continue with the pregnancy. Several fetal ultrasonographic studies (US) during early pregnancy showed normal fetal growth. Amniocentesis and US at 17th week showed normal chromosomes (46,XX) and growth. The long bones were then measured and considered to be within normal length for age. However, a t 27 weeks of gestation a scheduled US showed short humeri, compatible with a mean length found at the 20th week of gestation. Other long bones were all normal for gestational age. After that, the growth of long bones, except the humeri, was on the 3rd centile. The humeri grew on the 4th standard deviation below the mean. Bipariatal diameter (BPD), head and chest circumference, and weight prediction were all within the expected range for the examined gestational age. No other fetal anomalies could be depicted ultrasonographically. Fetal roentgenograms (twofilms taken after informed consent was given) at.30 weeks gestation failed to document any well-defined, short-limb entity.
418
Borochowitz
centile), the outer canthal distance (OC)was 6 cm (25th centile). A. Peroxisomal disorders Forearms were apparently normal, tibiae and hands 1. Zellweger syndrome were mildly short with palm length 3 cm, middle finger 2. Rhizomelic chondrodysplasia punctata 2 cm (both on the 3rd centile). She also had clinodactyly B. Genetic disorders and camptodactyly of the 5th fingers, a bilateral simian 1. Conradi-Hunermann chondrodysplasia punctata 2. X-linked dominant chondrodysplasia punctata crease, hypoplastic nails of fingers and toes, normal 3. CHILD syndrome joint movements, normal skin normal neurological find4.GM1 gangliosidosis ings. Immunological studies showed IgG antibody levels 5. Mucolipidosis I1 to VZ of above 1:80 and IgM below 1:10.TORCHEStiters 6. Chromosome translocation were nonreactive. Results of liver, renal, and thyroid 7. Trisomy 21 and 18 function tests were all normal; brain ultrasound was 8. Tibial-metacarpal chondrodysplasia punctata C. Vitamin K disorders normal. 1. Warfarin embryopathy Radiological findings a t this age documented a nor2. Vitamin K epoxide reductase deficiency mal skull and normal craniofacial relationships. The D. Acquired in utero nasal bone was extremely prominent. Face and mandi1.Fetal alcohol ble showed very mild disproportion with a mildly hypo2. Phenacetin plastic mandible. Stippling was noted in the thyroid and 3. Hydantoin E. Other pharyngeal region (Fig. 1). The clavicles and ribs were 1. Brachytelephalangic chondrodysplasia punctata normally formed. The spine showed minimal coronal 2. Cerebrocostomandibular syndrome clefts involving mainly the lower thoracic vertebral 3. Dysplasia epiphysealis hemimelica bodies. 4.Calcifying arthritis The upper limbs showed symmetrical shortness of humeri, which were also abnormal in contour. Elbows, A Cesarian section, due to early labor contractions radii, and ulnae were normal (Fig. 2). Hypoplasia of the and a high risk pregnancy, was performed at the 35th metacarpal region was noted. Stippling was noted in week. Apgar scores were 919 at 1 and 5 min, respectively. many of the metacarpals, especially in the metaphyseal Birth weight was 1,700 g, head circumference (OFC) and diaphyseal regions rather than in the epiphyseal was 30 cm (both 2 SD below the mean for age), and areas. The 4th metacarpals were the most severely affected (Fig. 3). The same changes were noted in the foot length was 40 cm (3 SD below the mean). At 3 days, short humeri were apparent and scap- films. Remarkable stippling occurred in the spine, espehocephaly, prominent occiput, round face, small nose cially in the sacral region (Fig. 4)The pelvis, ischium, with depressed nasal bridge, retrognathia, and thin up- and pubis were normal. The €emora were normal in per lip. Her inner canthal distance (IC) was 2.2 cm and length and configuration. The tibiae and the fibulae interpupillary distance (IP) was 4 cm (both on the 50th were normal in length. No stippling was seen in that TABLE I. Causes of Stippled Cartilagenous Calcifications
Fig. 1. Roentgenogram of the skull at age 3 days showing a mildly hypoplastic mandible, prominent nasal bone, and punctate calcifications in the thyroid cartilage and the pharyngeal regions (arrow).
Chondrodysplasia Punctata-New
Form
419
Fig. 3. Roentgenogram of the hands at birth short metacarpals (especially the 4th), stippling a t the metaphyseal region of several metacarpals, and the hypoplastic distal phalanges of the 2nd through 4th fingers
Fig. 2. A total body roentgenogram at age 3 days with rhizomelic shortness of humeri but normal radius, ulna, and femora.
region. Talus and calcaneus were ossified with some stippling involving the talus. A recent reexamination at 2112 years showed a healthy, normally developed child who attended a regular kindergarten (Fig. 5a,b). Measurements: Height OFC Palm Middle finger Inner canthal Outer canthal Interpupillary
cm 85 46 5.3 3.2 2.5 8.2 4.7
centile 10 3
Generalized Chondrodysplasia Punctata With Shortness of Humeri and Brachymetacarpy: HumeroMetacarpal (HM) Type: Variation or Heterogeneity? Zvi Borochowitz Simon Winter Center for Human Genetics, Bnai-Zion Medical Center, Technion-Faulty of Medicine, Haifa, Israel
We report on a girl with symmetrical rhizomelic shortness of the upper limbs and punctate epiphyseal calcifications noted at birth. Presumably she has normal height, but short nose, short hands, and normal mentation; and on roentgenograms short and wide humeri, symmetrical brachymetacarpy, especially of the 4th metacarpals, and hypoplastic distal phalanges, sagittal clefting of vertebral bodies, and punctate calcificationsat various areas including the entire spine, sacrum, hands, feet, trachea, and thyroid cartilage. It is an apparently new syndrome of chondrodysplasia punctata (CP), quite distinct from the classic form (Conradi-Hunermann type), as well as the other well-definedforms of CP. We thus suggest the term chondrodysplasia punctata, humero-metacarpal (HM) type. KEY WORDS chondrodysplasia punctata, punctate epiphyseal calcifications, short humeri, short metacarpals, skeletal dysplasia INTRODUCTION We report on an apparently undescribed variety of symmetrical rhizomelic upper limb dysplasia with punctate epiphyseal calcifications. This is a sporadic case, appears to represent a previously apparently undescribed form of CP, quite distinct from the classic form (Conradi-Hunermann type) [Spranger et al., 19711, as well as other forms of CP and variety of other diseases (Table I) [Gilbert et al., 1976; Happle, 1977, 1980; Burck, 1982; Badois et al., 1983; Curry et al., 1984; Pauli et al., 1987; Burton and
Received for publication May 24, 1990; revision received April 19, 1991. Address reprint request to Dr. Z. Borochowitz, Director, Simon Winter Center for Human Genetics, Bnai-Zion Medical Center, Box 4940, Haifa 31048, Israel.
0 1991 Wiley-Liss, Inc.
Oestreich, 1988;Maroteaux et al., 1989;Lawrence et al., 1989; Rittler et al., 19901.
CLINICAL REPORT The girl was the second child born to her AshkenaziJewish parents. Consanguinity was denied. The mother, age 26, was known to have an uncomplicated insulindependent diabetes mellitus (IDDM)onset at the age of 16 years. Therefore both of her pregnancies were monitored carefully in a tertiary maternal-fetal center. A healthy boy was the outcome of the previous, uncomplicated pregnancy. The father, age 28, was healthy. No other individuals in either family were known to have IDDM, short limbs, or any genetic disorder. Maternal diabetes was well controlled from the beginning and throughout this pregnancy. Maternal hemoglobin Al, level was below 8.5%since early pregnancy and was consideredwithin the accepted normal range for a teratogenic risk [Miller et al., 19811. At 7-8 weeks of gestation the mother developed mild varicella zoster (VZ). It was diagnosed by the presence of a few varicella eruptions found on her upper limbs, chest, and face. Body temperature was above normal only during the first day of illness, rising to a maximum level of 38.2"C. Genetic counselling mainly emphasized IDDM and early-gestational varicella zoster. The couple elected to continue with the pregnancy. Several fetal ultrasonographic studies (US) during early pregnancy showed normal fetal growth. Amniocentesis and US at 17th week showed normal chromosomes (46,XX) and growth. The long bones were then measured and considered to be within normal length for age. However, a t 27 weeks of gestation a scheduled US showed short humeri, compatible with a mean length found at the 20th week of gestation. Other long bones were all normal for gestational age. After that, the growth of long bones, except the humeri, was on the 3rd centile. The humeri grew on the 4th standard deviation below the mean. Bipariatal diameter (BPD), head and chest circumference, and weight prediction were all within the expected range for the examined gestational age. No other fetal anomalies could be depicted ultrasonographically. Fetal roentgenograms (twofilms taken after informed consent was given) at.30 weeks gestation failed to document any well-defined, short-limb entity.
418
Borochowitz
centile), the outer canthal distance (OC)was 6 cm (25th centile). A. Peroxisomal disorders Forearms were apparently normal, tibiae and hands 1. Zellweger syndrome were mildly short with palm length 3 cm, middle finger 2. Rhizomelic chondrodysplasia punctata 2 cm (both on the 3rd centile). She also had clinodactyly B. Genetic disorders and camptodactyly of the 5th fingers, a bilateral simian 1. Conradi-Hunermann chondrodysplasia punctata 2. X-linked dominant chondrodysplasia punctata crease, hypoplastic nails of fingers and toes, normal 3. CHILD syndrome joint movements, normal skin normal neurological find4.GM1 gangliosidosis ings. Immunological studies showed IgG antibody levels 5. Mucolipidosis I1 to VZ of above 1:80 and IgM below 1:10.TORCHEStiters 6. Chromosome translocation were nonreactive. Results of liver, renal, and thyroid 7. Trisomy 21 and 18 function tests were all normal; brain ultrasound was 8. Tibial-metacarpal chondrodysplasia punctata C. Vitamin K disorders normal. 1. Warfarin embryopathy Radiological findings a t this age documented a nor2. Vitamin K epoxide reductase deficiency mal skull and normal craniofacial relationships. The D. Acquired in utero nasal bone was extremely prominent. Face and mandi1.Fetal alcohol ble showed very mild disproportion with a mildly hypo2. Phenacetin plastic mandible. Stippling was noted in the thyroid and 3. Hydantoin E. Other pharyngeal region (Fig. 1). The clavicles and ribs were 1. Brachytelephalangic chondrodysplasia punctata normally formed. The spine showed minimal coronal 2. Cerebrocostomandibular syndrome clefts involving mainly the lower thoracic vertebral 3. Dysplasia epiphysealis hemimelica bodies. 4.Calcifying arthritis The upper limbs showed symmetrical shortness of humeri, which were also abnormal in contour. Elbows, A Cesarian section, due to early labor contractions radii, and ulnae were normal (Fig. 2). Hypoplasia of the and a high risk pregnancy, was performed at the 35th metacarpal region was noted. Stippling was noted in week. Apgar scores were 919 at 1 and 5 min, respectively. many of the metacarpals, especially in the metaphyseal Birth weight was 1,700 g, head circumference (OFC) and diaphyseal regions rather than in the epiphyseal was 30 cm (both 2 SD below the mean for age), and areas. The 4th metacarpals were the most severely affected (Fig. 3). The same changes were noted in the foot length was 40 cm (3 SD below the mean). At 3 days, short humeri were apparent and scap- films. Remarkable stippling occurred in the spine, espehocephaly, prominent occiput, round face, small nose cially in the sacral region (Fig. 4)The pelvis, ischium, with depressed nasal bridge, retrognathia, and thin up- and pubis were normal. The €emora were normal in per lip. Her inner canthal distance (IC) was 2.2 cm and length and configuration. The tibiae and the fibulae interpupillary distance (IP) was 4 cm (both on the 50th were normal in length. No stippling was seen in that TABLE I. Causes of Stippled Cartilagenous Calcifications
Fig. 1. Roentgenogram of the skull at age 3 days showing a mildly hypoplastic mandible, prominent nasal bone, and punctate calcifications in the thyroid cartilage and the pharyngeal regions (arrow).
Chondrodysplasia Punctata-New
Form
419
Fig. 3. Roentgenogram of the hands at birth short metacarpals (especially the 4th), stippling a t the metaphyseal region of several metacarpals, and the hypoplastic distal phalanges of the 2nd through 4th fingers
Fig. 2. A total body roentgenogram at age 3 days with rhizomelic shortness of humeri but normal radius, ulna, and femora.
region. Talus and calcaneus were ossified with some stippling involving the talus. A recent reexamination at 2112 years showed a healthy, normally developed child who attended a regular kindergarten (Fig. 5a,b). Measurements: Height OFC Palm Middle finger Inner canthal Outer canthal Interpupillary
cm 85 46 5.3 3.2 2.5 8.2 4.7
centile 10 3
