February 4-18, 2000

Submitted and discussed by Gerald Mulligan, MD, Marshfield, Wisconsin, USA and Philippe Jeanty, MD, PhD

These are several images from a 27-week and 29-week 1/2 examination. The mother is a 32 y/o G5 P4 woman with three normal children and one prior affected child. She was not felt to have the syndrome herself, but had not completely been evaluated. This fetus was sent to us for a question of subcutaneous edema on an outside study.

Review of the images

Axial image over the chest: Gain settings were set relative high to enhance the skin-amniotic fluid interface.  It shows a fine specular line typical for fine hair (i.e. hirsutism).  This was a critical finding and was recognized only by a few readers. While it"s not the greatest image, a high VSD is also seen.

Heart image showing a small size to pulmonary artery (i.e. stenosis).  Compare to the next image that demonstrates a normal sized ascending aorta.

Heart image with the normal size ascending aorta. Compare to the small pulmonary artery on the previous image.

Heart image showing high ventricular septal defect with overriding aorta.  Note that the fine hair over the chest is also seen, but subtler with the regular gain settings.  The child had a typical Tetralogy of Fallot.

Axial image at the left eye shows the long eyelashes of one eye. This is another critical finding that very few observed.

Axial image at the right eye shows the long eyelashes of the other eye. I bet that from now on, you will not miss that finding!

Midline sagittal image at the genitalia of this little boy showing the scrotum but no real penile shaft.  The child was male with a micropenis.

Transverse image at the genitalia showing a central grooved scrotum but no real penile shaft.

Hand: Unusual position of the fingers, I thought it showed a syndactyly of the third and forth fingers.  On physical exam post delivery, there was mild syndactyly present between those fingers, but the major reason for the finding was contractures.

Additional findings that were not included in the pictures were:

1.      Slightly small feet for body habitus and

2.      Possibly a hiatal hernia.

3.      The child"s chin was normal sized.

4.      The extremities were in the lower range of normal for length.

5.      No nuchal thickening was present.

6.      Between an outside 23-week study and the 29.5-week exam there was a slight fall off in growth.  The calculated incremental weight gain was 80% of the expected to parallel the normal curve.  The weight of 1,335 was only just below the 50th% however at 29.5 weeks.

As expected the combination of multiple findings in multiple organ system should raise the suspicion of aneuploidy (and many suggested trisomy 13 and 18) or a syndrome (and Noonan and Smith-Lemli-Opitz were popular choice).

The beauty of this case is to clearly demonstrate an obvious finding—obvious only when looked for. This is the reason I mentioned in the announcement to “remember the quote on the Frontispiece of the Case of the Week”: “People only see what they are prepared to see.” (Ralph Waldo Emerson)

Clearly the most unusual finding in this baby is the long eyelashes and the hairs on the chest. So the easiest way to approach this diagnostic is to search on these findings. This is an interesting exercise for those not used to use the web for differential diagnoses.

The easiest approach is to go to Medline (on the main page, under Tools) and do a search on “long eyelashes”. To limit the number of articles add “newborn” (using “fetus” often limits too much the differential diagnoses). These are the articles that include those criteria:

Am J Med Genet 1993 Nov 15;47(7):940-6de Lange syndrome: a clinical review of 310 individuals.Jackson L, Kline AD, Barr MA, Koch SDepartment of Medicine, Jefferson Medical College, Philadelphia, Pennsylvania.Three hundred ten individuals with a clinical diagnosis of de Lange syndrome were seen and examined in conjunction with the parent support group. One hundred thirty-four males and 176 females whose ages ranged from birth to 37 years made up the study group. Examination findings were recorded for those features described by de Lange in her original report of the syndrome to determine the frequency and significance of each. In addition, questionnaires were completed by 128 of these families and medical, growth and developmental records were collected. The clinical diagnosis seems best supported by the facial features of the syndrome including the long eyelashes and confluent eyebrows (synophrys), although additional characteristics are needed. Only 27% had the upper limb deficiencies commonly associated with the syndrome. Growth was retarded in nearly all individuals, often of prenatal onset. Medical problems occurred frequently and most often involved the eye and ear, as well as the cardiac and gastrointestinal systems. Of 14 deaths, almost half were secondary to cardiac or gastrointestinal complications. The recurrence risk in 377 sibs of the patients was calculated to be less than 1%. Although development lagged significantly in speech, most individuals developed good self-help skills. The study demonstrated a higher proportion of patients affected mildly with the syndrome than is commonly appreciated. This underscores the importance of early recognition and appropriate medical and developmental support.

Virchows Arch A Pathol Anat Histopathol 1988;413(5):463-8Cornelia de Lange syndrome associated with Wilms" tumour and infantile haemangioendothelioma of the liver: report of two autopsy cases.Maruiwa M, Nakamura Y, Motomura K, Murakami T, Kojiro M, Kato M, Morimatsu M, Fukuda S, Hashimoto TFirst Department of Pathology, Kurume University School of Medicine, Japan.Two cases of Cornelia de Lange syndrome associated with infantile haemangioendothelioma of the liver and Wilms" tumour are reported. The patients showed the characteristic facies of the Cornelia de Lange syndrome, with synophrys, long curly eyelashes and small upturned nose, and physical features, including generalized hirsutism, monodactyly, syndactyly and clinodactyly. Post-mortem examination revealed annular pancreas, patency of the foramen ovale, duodenal atresia and evidence of cytomegalic infection. The cases are reported to document a possible association between malformations and neoplasms in this syndrome.

J Pediatr Ophthalmol Strabismus 1981 Jul-Aug;18(4):6-15Fetal alcohol syndrome.Miller M, Israel J, Cuttone JSignificant alcohol ingestion during pregnancy can cause a spectrum of malformation of various degrees of severity in offspring. The full expression of "fetal alcohol syndrome" includes reduced growth, facial anomalies, and mental retardation. Affected infants are usually of near-term gestation, but small in weight and length. They continue to exhibit decreased growth postnatally. Mental retardation appears to be related to the degree of dysmorphic severity of appearance. It is primarily caused by central nervous system pathology rather than social environment. The most prevalent ophthalmologic finding in our series of a short horizontal palpebral fissure appears to be due primarily to a marked increased in intercanthal distances between the medial canthi (primary telecanthus) and to less extent mild displacement of the lateral canthi. Ptosis, often asymmetric, was noted in a number of patients. Comitant convergent strabismus was present in about 50% of our cases; a few had amblyopia. An important observation was the frequent and often high degree of myopia in these children. Low-incidence anomalies include corneal opacities (Peters anomaly in one), cataract, tortuosity of retinal vessels, and long eyelashes. Our findings plus many observations in the literature establish that children with fetal alcohol syndrome are at considerable risk for a variety of eye problems.PMID: 7264859, UI: 81266679

Ann Genet 1978 Dec;21(4):247-51[Trisomy 13qter by tandem duplication 46, XX, dir dup 13 (q21 qter), 9qh+].[Article in French]de Grouchy J, Turleau C, Danis F, Kohout G, Briard MLA tandem translocation of chromosome 13-46,XXdup13(q21 leads to qter)--occurred de novo in a patient with the following features: normal birthweight; early feeding difficulties; mild psychomotor retardation; low set hairline on the forehead; thick eyebrows; long, upturned eyelashes; pointed nose; micrognathia; large, flat, posteriorly rotated ears; multiple hemangiomata; normal hematological status. The hypothesis of an unequal crossing-over is discussed, as well as the possibility of constructing a phenotypic map of chromosome 13.

Hum Genet 1976 Apr 15;32(1):1-12Further delineation of the clinical picture of trisomy for the distal segment of chromosome 13: report of three cases.Schinzel A, Hayashi K, Schmid WThree cases of partial trisomy for the distal segment of chromosome 13 are reported. Common clinical features included normal birth weight, postnatal asphyxia, convulsions, severe psychomotor retardation, normal growth, and a distinct pattern of dysmorphias consisting of trigonocephalic head with prominent metopic suture, long and markedly curved eyelashes, a stubby nose, increased distance between nose and upper lip, high-arched palate, misshapen ears with virtually absent lobules and prominent anthelices which are curved in a sharp angle, and hemangiomata. Features present in 2 cases were microcephaly, long and narrow fingers with convex nails, and hexadactyly. Two cousins were unbalanced offspring of a large family of carriers of a 9/13 translocation, whereas the third case exhibited a 13p+ chromosome which was formed de novo. The clinical features in the 3 patients are typical of the syndrome due to partial trisomy for the distal segment of chromosome 13 which shows selected and mitigated signs of full trisomy 13.

Am J Hum Genet 1975 Nov;27(6):699-718Chromosome 3 duplication q21 leads to qter deletion p25 leads to pter syndrome in children of carriers of a pericentric inversion inv(3) (p25q21).Allderdice PW, Browne N, Murphy DPClose phenotypic similarity between two cases carrying a rec(3) dup q,inv(3) (p25q21), 12 additional infants from the same inv (3)(p25q21) kindred who lived less than 1 year, and eight cases studied in other medical centers has led us to postulate the existence of a distinct chromosome 3 duplication-deletion syndrome. In the presence of trisomy for (3)q21 leads to qter and monosomy for (3)p25 leads to pter, the facial dysmorphy is unique: a distorted head shape due to irregular cranial sutures, thick low eyebrows, long eyelashes, persistent lanugo, distended veins on the scalp, hypertelorism, oblique palpebral fissures, a very short nose with a broad depressed bridge and anteverted nares, protruding maxilla, thin upper lip, micrognathia, low-set ears, and a short webbed neck. Port-wine stains, congenital glaucoma, cloudy corneas, cleft palate and harelip also occur frequently. Each infant has difficulty sucking and swallowing. Congenital anomalies of the cardiovascular system, of midgut rotation, and of the urogenital system are noted for the infants who died neonatally. Most frequent is a ventricular septal defect, followed by atrial septal defect, patent ductus arteriosus, patent foramen ovale, and coarctation of the aorta. Omphalocele, umbilical hernia, hyperplastic kidneys, polycystic kidneys, double ureter, hydro-ureter, hydronephrosis, and undescended testes often occur. The extremities are short in proportion to the length of the trunk. Clinodactyly, coxa valga, talipes, and spina bifida are frequently observed.

A search on “long eyelashes hirsutism” brought the following 2 articles:

Eur J Pediatr 1991 Feb;150(4):250-2The Floating-Harbor syndrome.Majewski F, Lenard HGInstitute of Human Genetics, Dusseldorf, Federal Republic of Germany.We describe the seventh patient with the Floating-Harbor syndrome. Similar to previous cases in the literature this girl presented with proportionate intrauterine and postnatal growth retardation, normocephaly, triangular face with bulbous nose, long eyelashes, short upper lip, small vermilion border of upper lip, dorsally rotated ears, deep nuchal hair line, hirsutism, and clinodactyly of little fingers. She exhibited mental retardation and retarded speech development. Clinical symptoms and differential diagnosis of this rare syndrome are briefly discussed.

Virchows Arch A Pathol Anat Histopathol 1988;413(5):463-8Cornelia de Lange syndrome associated with Wilms" tumour and infantile haemangioendothelioma of the liver: report of two autopsy cases.Maruiwa M, Nakamura Y, Motomura K, Murakami T, Kojiro M, Kato M, Morimatsu M, Fukuda S, Hashimoto TFirst Department of Pathology, Kurume University School of Medicine, Japan.Two cases of Cornelia de Lange syndrome associated with infantile haemangioendothelioma of the liver and Wilms" tumour are reported. The patients showed the characteristic facies of the Cornelia de Lange syndrome, with synophrys, long curly eyelashes and small upturned nose, and physical features, including generalized hirsutism, monodactyly, syndactyly and clinodactyly. Post-mortem examination revealed annular pancreas, patency of the foramen ovale, duodenal atresia and evidence of cytomegalic infection. The cases are reported to document a possible association between malformations and neoplasms in this syndrome.

So up to now the big contenders (without even looking at the abstracts) include:

·        Cornelia de Lange syndrome

·        Fetal alcohol syndrome.

·        Partial defects of chromosome 13 and 3

·        The Floating-Harbor syndrome.

Medline is not good at providing descriptions of syndromes (these are abstracts of new reports, rarely synthesis of material). So the next site to use is OMIM (also under Tools).

Doing the same “long eyelashes hirsutism” search in OMIM provided only one differential diagnosis:

122470 CORNELIA DE LANGE SYNDROME 1; CDL1

So in practice the next step is to read the diagnosis that has emerged from these 2 sources and see if it fits the images at hand:

Cornelia de Lange Syndrome.