Circadian Rhythm - Temperature

QUESTION“How are you feeling?”

• Very drowsy and would love a little nap

• Wide Awake and rearing to go

• Asleep – do not disturb

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A Child with Failure to Thrive

Colin WallisRespiratory Unit

Great Ormond Street Hospital

• FTND - asymmetrical IUGR

• Birth weight 1.9 kgs < 0.4th centile

• Length 42 cms < 0.4th centile

• OFC 33.2cms > 25th centile

• Ventilated for 3 days and discharged home in air at 14 days

• FBC and serum biochemistry were normal

• TORCH screen - negative

• Some episodes of fasting hypoglycaemia

• No catch up growth despite adequate caloric intake via

• NGT feeds

Readmitted 10 days later to local hospital for poor weight gain and intermittent diarrhoea

Referred to GOSH for further investigations

QUESTION“What test is likely to be

most useful?”• Coeliac screen

• Endoscopy

• Sweat test

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Coeliac screen – negative

GI endoscopy and colonoscopy were normal including histology of large bowel

Sweat test - positive Na 60 mmol/l ; Cl 111 mmol/l

A diagnosis of Cystic Fibrosis was made

• CF genotype - R1162X/R1162X

• Stool elastase - < 15 mcg/g {>200mcg}

• Positive sweat test

•Usual multivitamin supplementation and prophylactic antibiotics

•Adequate caloric intake with creon supplementation

• Overnight NGT and top-up feeds

QUESTION“What next?”

• Remove ng tube and monitor weight gain

• Insert gastrostomy for long term feeding

• Consider diabetes

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• Ng tube was removed with very poor feeding and further loss of weight

• No evidence of diabetes

• Gastrostomy inserted at age 3 years

…… and so over the next 2 years ………….

•Overnight feeds with additional boluses during the day

•Persisting FTT with weight and height well below 0.4th centile and intermittent diarrhoea

•No chest infections - only growth of Ps. aeruginosa at 4 years of age

At 5 years :

Weight - 12 kgs <0.4th centile

Height - 95 cms <0.4th centile

FVC 117% of predicted

FEV1 117% of predicted

QUESTION“Does she deserve further

investigation?”• Yes – Endocrine review

• Yes – Gastroenterology review

• No – This needs psychosocial input

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For those of you who voted Endocrine:

• Skeletal survey at 5 yrs - delayed bone age 2.5 yrs

• Normal amino acid profile

• Growth hormone assay - normal

• Normal IGF1 & IGFBP-3

• Normal thyroid function tests

• Normal cortisol , insulin and glucose levels

• Normal NEFA and BOHB (rules out fatty acid oxidation

defects)

For those of you who voted Gastroenterology:

• Stool elastase still very low• pH study normal - pH study - 0.5% reflux• Repeat upper GI biopsies suggestive of duodenitis with

mucosal eosinophilic infiltrate • Started on MCT feeds (peptamen) & PO Sodium

cromoglycate

• Improved stool consistency with occasional diarrhoea

• Introduction of dairy free diet

…. And the failure to thrive persisted….

For those of you who voted Psychosocial:

• Psycho-social issues - Parental disharmony

• Father blamed mother for the CF in their child – refused to accept that he had a genetic role in the condition

• Suggested genetics counselling

• Full term gestation

• Birth weight & length <2SD below mean

• Postnatal growth <2SD below mean for height & weight

• Triangular face (Craniofacial disproportion)

• Down turned corners of mouth

• Clinodactyly, and usually shorter digit than normal

• Scaphocephaly

• Hypoplastic mandible and small, crowded teeth

• Low set, small, or prominent ears

• Delays in bone age and poor muscle tone

Phenotypically resembles Russell Silver Syndrome

Genetics review

Phenotypically resembles Russell Silver Syndrome

Phenotypically resembles Russell Silver Syndrome

Common traits:

• Body asymmetry

• Growth hormone deficiency

• Hypoglycaemia in infancy and early childhood

• Late closure of the fontanelle

• Hypoplastic mandible and small, crowded teeth

• Low set, small, or prominent ears

• Delays in bone age and poor muscle tone

• Thin upper lip with down turned corners of mouth

• Syndactyly of toes

• Developmental delay

Are you sure this is CF?

9 6 3

3132

46XX, homozygous for R1162X mutation

Mum – carrier for R1162X

Dad – not a carrier

QUESTION “How are you feeling now?”

• Glad I don’t have to explain non-paternity to this family

• Ask genetics to approach the family

• I’m staying well out of this

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9 6 3

3132

46XX, homozygous for R1162X mutation

Mum – carrier for R1162X

Dad – not a carrier

Dad is the father

Child has uniparental disomy

What is Uniparental Disomy?

•UPD is the inheritance of both homologues of a chromosome pair from only one parent.•In 2/3 of cases the UPD is of maternal origin.•UPD can result in:

–the appearance of recessive disorders depending on the chr.–developmental and growth abnormalities (due to imprinting)–no apparent impact on the health of the individual.

Genetics of Russell Silver Syndrome

• 10% of cases of RSS have maternal UPD7

• Genetically heterogeneous – 80% cases sporadic– (AD/AR/XL)

• RSS caused by matUPD7 gives a milder phenotype, but the feeding problems are more severe.

Normal Meiosis

• Start with a cell with 46 chromosomes

• Sister Chromatid formation

• Meiosis I: the homologous pairs separate into two new daughter cells.

• Meiosis II: the replicated pair of sister chromatids separates into two new daughter cells.

Meiotic Errors

Meiosis I error Meiosis II error

homologous pairs both travel into the same daughter cell.

chromatids will not separate and thus travel into the same daughter cell.

QUESTION“How does UPD occur?”

• By Trisomic rescue

• By Monosomic resuce

• Gamete complementation

• Don’t know what you’re on about

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How does UPD occur ?

: CF Mutation on 7q31.2

Trisomic RescueFertilisation

following Meiosis II error

Monosomic Rescue

Fertilisation following Meiosis II

error

Gamete Complementatio

n

How does UPD cause CF?

• Patient AA is homozygous for the R1162X (arginine-stop) mutation as she has inherited both chromosome 7’s from her mum.

• Children with this form of CF do not have normal AR risks for future pregnancies – recurrence risk very low

• Gasparini et al looked at the clinical course of 9 patients homozygous for this mutation:– Lung disease was mild-moderate– Higher rates of pseudomonas colonisation– Higher rates of ABPA– Pancreatic insufficiency was severe– And our patient also has Russell Silver syndrome

Lessons and questions from an interesting case

• UPD is a rare but possible cause of autosomal recessive disorders

• We should be suspicious of FTT in CF with Russell Silver phenotype – but should we screen CF patients with unusual growth retardation for matUPD7 ?

• Should we be doing parental tests on all homozygous CF children?

• Testing DNA from parents and child can potentially uncover nonpaternity. Should this be discussed as part of informed consent ?

• Do these findings introduce new treatment options?

• Growth hormone therapy

• Nebulised or systemic gentamicin

• Be aware