Syndromes and Photos

Question 1

Adams-Oliver syndrome

• Smith’s page 419
• Dysmorphology part 2.pptx (11 - 14)

1. What features are shown in the photos?
2. Name the syndrome and list its salient features.

Answer 1

2. Adams-Oliver syndrome

• Cutis aplasia congenita
  (over the posterior parietal or occipital region - most often over the posterior sagittal suture, with or without an underlying defect of bone; round-oval hairless scars are found in the parietal region of older individuals)
• Dilated, tortuous scalp veins
• Terminal transverse limb defects - unilateral/bilateral
  (variable degrees from mild including short fingers and small toenails to severe absence of part of the limb resembling amputation)
• Cutis marmorata telangiectatica congenita (CMTC)
  (capillary malformation in 20%)
  (CMTC is a network of superficial, persistently dilated small blood vessels, which creates a marbled or lattice-like appearance, also known as livedo reticularis. It usually becomes more prominent with strong emotions).
  (A key distinction between CM and CMTC is that the vascular dilatation of CMTC does not fade markedly with local warming.)
• Cardiac defects - almost any type
  (in 20% of individuals - ASD, VSD, Coarctation of the aorta, hypoplastic LV, hypoplastic RV, DORV, DOLV)
• Mild growth deficiency
  (3rd to 10th percentile)

Question 2

Adams-Oliver syndrome

• Smith’s page 419
• Dysmorphology part 2.pptx (11 - 14)

1. What features are shown in the photos?
2. Name the syndrome and list its occasional abnormalities.

Answer 2

2. Adams-Oliver syndrome

OCCASIONAL ABNORMALITIES:
Neurological abnormalities (examples): 
Encephalocele - Acrania - Microcephaly - PMG
Migration defects
Intracranial calcifications (often periventricular)
Intellectual disability 
Epilepsy
Spastic hemiplegia (cerebral palsy)

IUGR - Low IGF-1 levels - Partial GH deficiency - Small pituitary

Microphthalmia - Esotropia - Hypoplastic optic nerve
Cataracts - Rod dystrophy
Incomplete or abnormal retinal vasculature (including persistent fetal vasculature)
Cleft lip - Cleft palate - Micrognathia

Syndactyly - Clubfoot - Poland sequence
(the combination of unilateral aplasia of part of the pectoralis muscle and ipsilateral upper limb anomalies)

Supernumerary nipples
Chylothorax
Cutis aplasia congenita on trunk and limbs - thin hyperpigmented skin
Pulmonary and non-cirrhotic or idiopathic portal hypertension (with gastroesophageal variceal bleeding)

Duplicated collecting system - Imperforate hymen - Cryptorchidism

Question 3

Adams-Oliver syndrome

• Smith’s page 419
• Dysmorphology part 2.pptx (11 - 14)

1. What features are shown in the photos?
2. Name the syndrome.
3. Name the gene(s).
4. What is the inheritance pattern? Caveats?

Answer 3

2. Adams-Oliver syndrome

3.
NOTCH1 - AD
DLL4 - AD
ARHGAP31 - AD (GOF mutations)
RBPJ - AD
DOCK6 - AR   
EOGT - AR

4. Majority AD - Marked variable expressivity and incomplete penetrance in some cases, as such first degree relatives should be examined closely + X-rays hands and feet.

Question 4

Adams-Oliver syndrome

• Smith’s page 419
• Dysmorphology part 2.pptx (11 - 14)

1. What features are shown in the photos?
2. Name the syndrome.
3. What is the prognosis?
4. What surveillance is indicated and why?

Answer 4

2. Adams-Oliver syndrome
3. Excellent in vast majority of cases - lesions less than 5 cm often involve only the skin and almost always heal over a period of months (conservative management goals are to prevent infection and promote healing).

Larger scalp defects are associated with underlying defects of bone and an increased risk of meningitis, hemorrhage or thrombosis, and can result in death - if the SSS (superior sagittal sinus) or dura and exposed. In these cases early surgical intervention with grafting is indicated.

Many limb anomalies are not severe enough to require surgical or prosthetic intervention. Occupational therapy and/or physical therapy are used as needed to assist with limb functioning. Rarely, surgical intervention for hand malformations is indicated.

At least five children with AOS have died from refractory pulmonary hypertension (~1% risk), all in the first three years of life = pHTN is associated with high mortality.

4. Echocardiography annually until age three years for signs of pulmonary hypertension. *NB: Echocardiography should be performed even when clinical signs of congenital heart disease are absent.

Annual pediatric care, including neurologic examination and ongoing assessment of psychomotor development.

Annual assessment by pediatric ophthalmologist until age three years for evidence of abnormal retinal vascular development.

Baseline abdominal US: to look for liver or renal anomalies, and to check for splenomegaly and patency of the portal vein. Repeat in case of signs of portal hypertension in those with failure to thrive, persistent nausea, abdominal swelling, or black stools

Question 5

Adams-Oliver syndrome

• Smith’s page 419
• Dysmorphology part 2.pptx (11 - 14)

1. What features are shown in the photos?
2. Name the syndrome.
3. What sonographic features can be appreciated on prenatal ultrasound?
4. How is a diagnosis established?
5. What are the most frequently mutated AOS-related genes / least frequently?
6. For autosomal recessive AOS with neurologic and ocular abnormalities, what gene analysis may be particularly indicated?
7. What is the detection rate of sequencing?
8. Is there an established genotype-phenotype correlation?

Answer 5

2. Adams-Oliver syndrome

3. 
Microcephaly 
IUGR
Encephalocele 
Absent digits 
Club foot 
Cardiac defects 
? Dilated, tortuous placental blood vessels (GeneReviews)

4. The diagnosis of Adams-Oliver syndrome (AOS) is established in a proband with one of the following:

The clinical findings of both aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD)

Either ACC or TTLD and a first-degree relative with findings consistent with AOS

Either ACC or TTLD and either a pathogenic variant in an autosomal dominant AOS-related gene or biallelic pathogenic variants in an autosomal recessive AOS-related gene identified on molecular genetic testing.

5. For autosomal dominant or simplex (i.e., a single occurrence in a family) AOS: NOTCH1 and DLL4 are the most frequently mutated AOS-related genes.

Majority of cases: NOTCH1 gene (~23%)
Smallest number of cases: ARHGAP31 gene (<5%)

6.
For autosomal recessive AOS with neurologic and ocular abnormalities: DOCK6 analysis may be particularly indicated.

7.
Detection rate of sequencing is ≥99%.

8.
No genotype-phenotype correlations.

Question 6

Johanson-Blizzard syndrome
Insert Photos:
- Smith’s page 145
- Dysmorphology part 1.pptx (78 and 79)

1. List the features shown in the photos.
2. Name the syndrome and list its salient features.

Answer 6

1.

2.
Johanson-Blizzard syndrome
- Mild to moderate microcephaly (50%)
- IUGR (60%)
- Intellectual disability (frequently - which may be severe, but normal intellect has been documented)
- Prominent forehead 
- Frontal upsweep of hair pattern
- Midline scalp defect - cutis aplasia (typically posterior but can be anterior or over the vertex)

• Upslanting palpebral fissures
• Nasolacrimal duct cutaneous fistulae (supernumerary lacrimal canaliculi that connect the skin to the common lacrimal sac)
• Absence of superior or inferior lacrimal puncta causing epiphora (excessive watering of the eye)
• ‘Pinched’ or ‘beaked’ nose with hypoplastic/aplastic alae nasi (100%)
• Hypoplastic deciduous teeth (baby teeth); absent permanent teeth (90%)
• SNHL (75%)
• Hypothyroidism of unknown etiology (30%) - rarely noted in the neonatal period
• Exocrine pancreatic insufficiency with malabsorption (100%) - fecal elastase is a useful test of pancreatic exocrine function
• Hypotonia
• Genitourinary malformations
  (Caliectasis to hydronephrosis; vesicoureteral reflux)
  (Single urogenital orifice)
  (Septate vagina or double vagina)
  (Hypospadias - Micropenis - Cryptorchidism)
• Anorectal malformations
  (imperforate or anteriorly placed anus; rectourethral or rectovaginal fistula)

Question 7

Johanson-Blizzard syndrome
Insert Photos:
- Smith’s page 145
- Dysmorphology part 1.pptx (78 and 79)

1. List the features shown in the photos.
2. Name the syndrome and list its occasional abnormalities.

Answer 7

1.

2.
Johanson-Blizzard syndrome
OCCASIONAL ABNORMALITIES
Severe facial clefting
Eyelid colobomas - strabismus - cataracts
Small nipples - absent areolae
Radiolucent skull defects - Abnormal EEG
Arhinencephaly (agenesis of the olfactory bulbs and tracts, characterized by complete congenital anosmia)

Cardiac defects (septal defects, myxomatous mitral valve, and dilated cardiomyopathy)

Abdominal and thoracic situs inversus

Neonatal cholestasis

Urethral obstruction sequence (severe bladder distension by the end of the first trimester of pregnancy, resulting in renal dysplasia or hydronephrosis, oligohydramnios and subsequent lung hypoplasia)

Fifth finger clinodactyly - Transverse palmar crease

Café au lait spots

Diamond-Blackfan anemia

Growth hormone deficiency

Question 8

Johanson-Blizzard syndrome
Insert Photos:
- Smith’s page 145
- Dysmorphology part 1.pptx (78 and 79)

1. List the features shown in the photos.
2. Name the syndrome.
3. Name the gene(s).
4. What is the inheritance pattern?
5. What is the prognosis?
6. Is there an established genotype-phenotype correlation?

Answer 8

1.

2.
Johanson-Blizzard syndrome

3. UBR1
4. Autosomal recessive.
5. Improvement in growth rate may occur when the patient is treated with thyroid replacement, pancreatic enzymes, and fat-soluble vitamins.

Diabetes and loss of glucagon response to hypoglycemia develop in adolescence and adults as a result of ongoing destruction of the pancreas.

6. Missense mutations in the gene cause a milder phenotype than those that abolish gene function.

Question 9

Insert Photos:
- Dysmorphology part 2.pptx (58 and 59)

1. List the features shown in the photos.
2. Name the syndrome and list its salient features.
3. Name the gene(s).
4. What is the inheritance pattern?

Answer 9

2. Setleis syndrome
   - Bitemporal scalp defects = resembling forceps marks
   - Coarse, aged leonine appearance
   - Skin: Increased mobility of facial skin with redundant facial soft tissue and a rubbery feel of the nose and chin
   - Eyebrows slanted upward
   - Multiple rows of eyelashes or absent eyelashes
   - Periorbital puffiness and puckered skin about the eyes
   - Flat nasal bridge with a bulbous nasal tip
   - Inverted V contour of the mouth with large lips and downturned overly defined corners
   - Typically normal intelligence, but some may have developmental delay

3.
TWIST2 gene

4. Autosomal recessive

Question 10

Insert Photos:

• Dysmorphology part 2.pptx (56 and 57)
• Gorlin slides

1. List the features shown in the photos.
2. Name the syndrome and list its salient features.
3. Name the gene(s).
4. What is the inheritance pattern?

Answer 10

2. Oculo-cerebro-cutaneous Syndrome (Delleman syndrome)
   - Facial asymmetry
   - Eye abnormalities
   (microphthalmia/anophthalmia - orbital cysts - dermoid - ?teratoma - eyelid coloboma - nystagmus)
   - Notched nasal alae
   - Cleft palate
   - Focal dermal aplasia/hypoplasia (Punch-like skin defects)
   - Linear skin pigmentation
   - Skin tags (periorbital, face, thorax, rarely on trunk)
   - Postauricular crescent-shaped hypoplastic skin lesion
   - Cutis aplasia congenita (focal alopecia)
   - Characteristic brain malformations
   (frontal polymicrogyria, periventricular nodular heterotopia, and agenesis of the corpus callosum - distinguishes it from Goltz)
   - Dandy-Walker malformation
3. Gene unknown
4. Unknown, but the condition predominantly affects males.